title: The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptors as therapy for hormone-independent prostate and breast cancers.
abstract: Therapies for hormone-independent prostate and breast cancer are limited, with the effectiveness of the taxanes compromised by toxicity, lack of oral bioavailability and drug resistance. This study aims to identify and characterise new microtubule disruptors, which may have improved efficacy relative to the taxanes in hormone-independent cancer. 2-Methoxy-3-O-sulphamoyl-17beta-cyanomethyl-oestra-1,3,5(10)-triene (STX641), 2-methoxy-3-hydroxy-17beta-cyanomethyl-oestra-1,3,5(10)-triene (STX640) and 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140) were all potent inhibitors of cell proliferation in a panel of prostate and breast cancer cell lines. STX641 and STX640 significantly inhibited tumour growth in the MDA-MB-231 xenograft model. STX641 inhibited both in vitro and in vivo angiogenesis. Despite good in vivo activity, STX641 was not as potent in vivo as STX140. Therefore, STX140 was evaluated in the prostate hormone-independent PC-3 xenograft model. STX140 had superior efficacy to docetaxel, 2-MeOE2 and bevacizumab. In contrast to vinorelbine, no significant toxicity was observed. Furthermore, STX140 could be dosed daily over a 60-day period leading to tumour regression and complete responses, which were maintained after the cessation of dosing. This study demonstrates that STX641 and STX140 have considerable potential for the treatment of hormone-independent breast and prostate cancer. In contrast to the taxanes, STX140 can be dosed orally, with no toxicity being observed even after prolonged daily dosing.
authors.affiliation: Endocrinology and Metabolic Medicine and Sterix Ltd, Faculty of Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, UK. simon.newman@imperial.ac.uk
authors.forename: S P
authors.initials: SP
authors.lastname: Newman
authors.forename: P A
authors.initials: PA
authors.lastname: Foster
authors.forename: Y T
authors.initials: YT
authors.lastname: Ho
authors.forename: J M
authors.initials: JM
authors.lastname: Day
authors.forename: B
authors.initials: B
authors.lastname: Raobaikady
authors.forename: P G
authors.initials: PG
authors.lastname: Kasprzyk
authors.forename: M P
authors.initials: MP
authors.lastname: Leese
authors.forename: B V L
authors.initials: BV
authors.lastname: Potter
authors.forename: M J
authors.initials: MJ
authors.lastname: Reed
authors.forename: A
authors.initials: A
authors.lastname: Purohit
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000528:radiation effects; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000187:drug effects; D004963:Estrenes / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D050257:Tubulin Modulators / Q000627:therapeutic use*
chemical_list: C526437:2-methoxy-3-O-sulfamoyl-17-cyanomethylestra-1,3,5(10)-triene; C526438:2-methoxyestradiol-3,17-O,O-bis(sulfamate); D020533:Angiogenesis Inhibitors; D004963:Estrenes; D050257:Tubulin Modulators