title: An in vitro model that can distinguish between effects on angiogenesis and on established vasculature: actions of TNP-470, marimastat and the tubulin-binding agent Ang-510.
abstract: In anti-cancer therapy, current investigations explore the possibility of two different strategies to target tumor vasculature; one aims at interfering with angiogenesis, the process involving the outgrowth of new blood vessels from pre-existing vessels, while the other directs at affecting the already established tumor vasculature. However, the majority of in vitro model systems currently available examine the process of angiogenesis, while the current focus in anti-vascular therapies moves towards exploring the benefit of targeting established vasculature as well. This urges the need for in vitro systems that are able to differentiate between the effects of compounds on angiogenesis as well as on established vasculature. To achieve this, we developed an in vitro model in which effects of compounds on different vascular targets can be studied specifically. Using this model, we examined the actions of the fumagillin derivate TNP-470, the MMP-inhibitor marimastat and the recently developed tubulin-binding agent Ang-510. We show that TNP-470 and marimastat solely inhibited angiogenesis, whereas Ang-510 potently inhibited angiogenesis and caused massive disruption of newly established vasculature. We show that the use of this in vitro model allows for specific and efficient screening of the effects of compounds on different vascular targets, which may facilitate the identification of agents with potential clinical benefit. The indicated differences in the mode of action between marimastat, TNP-470 and Ang-510 to target vasculature are illustrative for this approach.
authors.affiliation: Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jens
authors.initials: J
authors.lastname: van Wijngaarden
authors.forename: Thomas J A
authors.initials: TJ
authors.lastname: Snoeks
authors.forename: Ermond
authors.initials: E
authors.lastname: van Beek
authors.forename: Henny
authors.initials: H
authors.lastname: Bloys
authors.forename: Eric L
authors.initials: EL
authors.lastname: Kaijzel
authors.forename: Victor W M
authors.initials: VW
authors.lastname: van Hinsbergh
authors.forename: Clemens W G M
authors.initials: CW
authors.lastname: Löwik
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects* / Q000254:growth & development; D003510:Cyclohexanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology
chemical_list: C547502:Ang-510; D020533:Angiogenesis Inhibitors; D001555:Benzene Derivatives; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009943:Organophosphorus Compounds; D012717:Sesquiterpenes; D050257:Tubulin Modulators; C100342:marimastat; D000077609:O-(Chloroacetylcarbamoyl)fumagillol