title: Identification of human-selective analogues of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA).
abstract: BACKGROUND
  Species selectivity of DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) for murine cells over human cells could explain in part the recent disappointing phase III trials clinical results when preclinical studies were so promising. To identify analogues with greater human clinical potential, we compared the activity of xanthenone-4-acetic acid (XAA) analogues in murine or human cellular models.
  
  
  METHODS
  Analogues with a methyl group systematically substituted at different positions of the XAA backbone were evaluated for cytokine induction in cultured murine or human leukocytes; and for anti-vascular effects on endothelial cells on matrigel. In vivo antitumour activity and cytokine production by stromal or cancer cells was measured in human A375 and HCT116 xenografts.
  
  
  RESULTS
  Mono-methyl XAA analogues with substitutions at the seventh and eighth positions were the most active in stimulating human leukocytes to produce IL-6 and IL-8; and for inhibition of tube formation by ECV304 human endothelial-like cells, while 5- and 6-substituted analogues were the most active in murine cell systems.
  
  
  CONCLUSIONS
  Xanthenone-4-acetic acid analogues exhibit extreme species selectivity. Analogues that are the most active in human systems are inactive in murine models, highlighting the need for the use of appropriate in vivo animal models in selecting clinical candidates for this class of compounds.
authors.affiliation: Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, School of Medicine, University of Auckland, Auckland, New Zealand.
authors.forename: S M
authors.initials: SM
authors.lastname: Tijono
authors.forename: K
authors.initials: K
authors.lastname: Guo
authors.forename: K
authors.initials: K
authors.lastname: Henare
authors.forename: B D
authors.initials: BD
authors.lastname: Palmer
authors.forename: L-C S
authors.initials: LC
authors.lastname: Wang
authors.forename: S M
authors.initials: SM
authors.lastname: Albelda
authors.forename: L-M
authors.initials: LM
authors.lastname: Ching
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011509:Proteoglycans / Q000378:metabolism; D014966:Xanthenes / Q000737:chemistry / Q000494:pharmacology*; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D015850:Interleukin-6; D016209:Interleukin-8; D007797:Laminin; D011509:Proteoglycans; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; C059485:matrigel; C066138:xanthenone-4-acetic acid; D003094:Collagen