title: Methyl tert butyl ether is anti-angiogenic in both in vitro and in vivo mammalian model systems.
abstract: Methyl-tertiary butyl ether (MTBE), a well known gasoline oxygenate, and US Food and Drug Administration approved gallstone treatment, has been previously shown to specifically target teleost embryonic angiogenesis. The studies reported here were to determine whether similar vascular disrupting effects occur in higher vertebrate models. Rat brain endothelial cells were isolated and allowed to form microcapillary-like tubes on Matrigel. MTBE (0.34-34.0 mm) exposure resulted in a dose-dependent reduction of tube formation, with the LOAEL at 0.34 mm, while MTBE's primary metabolite, tertiary butyl alcohol had no effect on tube formation. HUVECs, a primary cell line representing macrovascular cells, were able to form tubes on Matrigel in the presence of MTBE (1.25-80 mm), but the tubes were narrower than those formed in the absence of MTBE. In a mouse Matrigel plug implantation assay, 34.0 mm MTBE completely inhibited vessel invasion into plugs containing endothelial cell growth supplement (ECGS) compared with control plugs with ECGS alone. When timed-pregnant Fisher 344 rats were gavaged with MTBE (500-1500 mg kg(-1) ) from day 6 of organogenesis through 10 days post-parturition, no organ toxicity or histological changes in pup vasculature were observed. Results of the in vitro cell culture studies show that MTBE is anti-angiogenic at mm concentrations and has potential use as an anti-angiogenic treatment for solid tumors with minimal toxicity.
authors.affiliation: Environmental Science, Rutgers University, New Brunswick, NJ, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kozlosky
authors.forename: Josephine
authors.initials: J
authors.lastname: Bonventre
authors.forename: Keith
authors.initials: K
authors.lastname: Cooper
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008738:Methyl Ethers / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D020002:tert-Butyl Alcohol / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D008738:Methyl Ethers; C043243:methyl tert-butyl ether; D020002:tert-Butyl Alcohol