title: Colchicine and 2-methoxyestradiol Inhibit Human Angiogenesis.
abstract: BACKGROUND
  Angiogenesis is a critical determinant of tumor growth and the development of metastases. Tubulin inhibitors have been shown to be effective inhibitors of angiogenesis. We hypothesized that colchicine, a well-know tubulin inhibitor and 2-methoxyestradiol (2 MeOH), a novel tubulin inhibitor, would limit the initiation of a human angiogenic response and would limit subsequent neovessel growth in a dose-dependent manner.
  
  
  METHODS
  To test this hypothesis, we cultured full-thickness human placental vein discs from three placentas in a fibrin-thrombin clot model. Both colchicine and 2 MeOH were tested over a wide range of concentrations (10(-6) to 10(-12) M) to determine their effect on the percent of wells that initiated an angiogenic response (%I) and the subsequent growth (Angiogenic Index, 0-16 range) of vein-derived neovessels.
  
  
  RESULTS
  Colchicine at doses of 10(-6) and 10(-8) M completely inhibited the angiogenic response (CI: 95%, P < 0.0001) but lower (10(-10) to 10(-12) M) doses did not significantly inhibit angiogenesis (P = NS). Effective in vitro colchicine levels far exceed achievable non-toxic human plasma levels. In contrast, 2-methoxyestradiol decreased initiation and angiogenic growth significantly at 10(-6) M (CI: 95%, P < 0.0001), but did not significantly decrease angiogenesis at doses of 10(-8), 10(-10), or 10(-12) M. In contrast to colchicine, human plasma levels of 10(-6) M 2 MeOH are achievable clinically with little or no associated toxicity.
  
  
  CONCLUSIONS
  Effective in vitro drug levels of 2 MeOH can be achieved in vivo, suggesting that 2 MeOH may have a role in the clinical treatment of angiogenesis-dependent diseases.
authors.affiliation: Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Stafford
authors.forename: J
authors.initials: J
authors.lastname: Schwimer
authors.forename: C T
authors.initials: CT
authors.lastname: Anthony
authors.forename: J L
authors.initials: JL
authors.lastname: Thomson
authors.forename: Y Z
authors.initials: YZ
authors.lastname: Wang
authors.forename: E A
authors.initials: EA
authors.lastname: Woltering
mesh_terms: D000077584:2-Methoxyestradiol; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D003078:Colchicine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D010920:Placenta / Q000098:blood supply
chemical_list: D020533:Angiogenesis Inhibitors; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003078:Colchicine