title: In vivo and in vitro properties of STX2484: a novel non-steroidal anti-cancer compound active in taxane-resistant breast cancer.
abstract: BACKGROUND
  STX2484 is a novel non-steroidal compound with potent anti-proliferative activity. These studies aimed to identify STX2484's mechanism of action, in vivo efficacy and activity in taxane-resistant breast cancer models.
  
  
  METHODS
  Effects of STX2484 and paclitaxel on proliferation, cell cycle and apoptosis were assessed in vitro in drug-resistant (MCF-7(DOX)) and non-resistant cells (MCF-7(WT)). STX2484 efficacy in βIII tubulin overexpression in MCF-7 cells was also determined. Anti-angiogenic activity was quantified in vitro by a co-culture model and in vivo using a Matrigel plug assay. An MDA-MB-231 xenograft model was used to determine STX2484 efficacy in vivo.
  
  
  RESULTS
  STX2484 is a tubulin disruptor, which induces p53 expression, Bcl2 phosphorylation, caspase-3 cleavage, cell cycle arrest and apoptosis. In addition, STX2484 is a potent anti-angiogenic agent in vitro and in vivo. In breast cancer xenografts, STX2484 (20 mg kg(-1) p.o.) suppressed tumour growth by 84% after 35 days of daily dosing, with limited toxicity. In contrast to paclitaxel, STX2484 efficacy was unchanged in two clinically relevant drug-resistant models.
  
  
  CONCLUSIONS
  STX2484 is an orally bioavailable microtubule-disrupting agent with in vivo anti-angiogenic activity and excellent in vivo efficacy with no apparent toxicity. Crucially, STX2484 has superior efficacy to paclitaxel in models of clinical drug resistance.
authors: 1] Oncology Drug Discovery Group, Section of Investigative Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK [2] Cancer Institute, UCL, 72 Huntley Street, London WC1E 6BT, UK.
authors: C
authors: C
authors: Stengel
authors: Oncology Drug Discovery Group, Section of Investigative Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors: S P
authors: SP
authors: Newman
authors: Oncology Drug Discovery Group, Section of Investigative Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors: J M
authors: JM
authors: Day
authors: Oncology Drug Discovery Group, Section of Investigative Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors: S K
authors: SK
authors: Chander
authors: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors: F L
authors: FL
authors: Jourdan
authors: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors: M P
authors: MP
authors: Leese
authors: Systems Biology, IPSEN, 5 Avenue du Canada, Les Ulis 91966, France.
authors: E
authors: E
authors: Ferrandis
authors: Systems Biology, IPSEN, 5 Avenue du Canada, Les Ulis 91966, France.
authors: S
authors: S
authors: Regis-Lydi
authors: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors: B V L
authors: BV
authors: Potter
authors: Oncology Drug Discovery Group, Section of Investigative Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors: M J
authors: MJ
authors: Reed
authors: Oncology Drug Discovery Group, Section of Investigative Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
authors: A
authors: A
authors: Purohit
authors: 1] Oncology Drug Discovery Group, Section of Investigative Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, UK [2] Centre for Endocrinology, Diabetes, and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK.
authors: P A
authors: PA
authors: Foster
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology*; D013451:Sulfonic Acids / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C000592930:2-(3,4,5-trimethoxybenzyl)-6-O-sulphamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline; D000972:Antineoplastic Agents, Phytogenic; D007546:Isoquinolines; D013451:Sulfonic Acids; D017239:Paclitaxel