title: Alterations in eicosanoid levels during U937 bcl-xL tumour growth suppression and recovery in NU/NU mice in vivo-Involvement of phospholipase A2.
abstract: We report the effects of two anti-cancer drugs, PBT-4, an experimental antagonist to the pro-inflammatory hepoxilins, and Gleevec (STI-571), an anti-leukaemic drug, on eicosanoid tumour levels in immunodeficient mice (NU/NU) xenografted with the leukaemic cell line, U937 bcl-xL. After the tumours had grown to 80-100mm(3) volume, an 8-day treatment with the drugs was initiated and the animals were monitored for 28 days. On various days, tumours were removed for measurement of 24 omega-6 eicosanoids. The data show remarkable direct correlation between inhibition of tumour AA release and 12-LOX products (including 12-HETE and hepoxilins) during PBT or STI treatment with tumour growth suppression. These findings suggest that inhibition of AA release may represent a novel underlying mechanism of action of PBT-4 (and STI) in vivo in suppressing tumour growth. As the PBT wears off, AA and 12-LOX products rise rapidly (Day 18) leading to the observed tumour growth spurt.
authors.affiliation: Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, Canada; Department of Pharmacology, Faculty of Medicine, University of Toronto, ON, Canada. Electronic address: pace@sickkids.ca.
authors.forename: Cecil R
authors.initials: CR
authors.lastname: Pace-Asciak
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Denis
authors.initials: D
authors.lastname: Reynaud
authors.forename: Na
authors.initials: N
authors.lastname: Qiao
authors.forename: Peter
authors.initials: P
authors.lastname: Demin
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdelhaleem
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D054467:Phospholipases A2 / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: C454100:10-hydroxy-11,12-cyclopropyleicosa-5,8,14-trienoic acid methyl ester; D000970:Antineoplastic Agents; D051020:bcl-X Protein; D016718:Arachidonic Acid; D054467:Phospholipases A2; D015126:8,11,14-Eicosatrienoic Acid
keywords: Antagonists; Eicosanoids; Hepoxilins; LCMSMS; Phospholipase; Tumours