title: Anti-angiogenic Effects of Bumetanide Revealed by DCE-MRI with a Biodegradable Macromolecular Contrast Agent in a Colon Cancer Model.
abstract: OBJECTIVE
  To assess the antiangiogenic effect of bumetanide with dynamic contrast enhanced (DCE)-MRI and a biodegradable macromolecular MRI contrast agent.
  
  
  METHODS
  A new polydisulfide containing macrocyclic gadolinium (Gd(III)) chelates, poly([(Gd-DOTA)-DETA]-co-DTBP) (GODP), was synthesized as a safe biodegradable macromolecular MRI contrast agent for DCE-MRI. Nude mice bearing flank HT29 colon cancer xenografts were then treated daily with either bumetanide or saline for a total of 3 weeks. DCE-MRI was performed before and after the treatment weekly. The DCE-MRI data were analyzed using the adiabiatic approximation to the tissue homogeneity (AATH) model to assess the change of tumor vascularity in response to the treatment. Immunohistochemistry (IHC) and western blot were performed to study tumor angiogenic biomarkers and hypoxia.
  
  
  RESULTS
  DCE-MRI with GODP revealed that bumetanide reduced vascular permeability and plasma volume fraction by a significantly greater extent than the saline control therapy after 3 weeks of therapy. These changes were verified by the significant decline of CD31 and VEGF expression in the bumetanide treatment group. Despite a significant regression in vascularity, the tumors remained highly proliferative. Overexpression of the transcription factor HIF-1α in response to elevated hypoxia is thought to be the driving force behind the uninterrupted tumor expansion.
  
  
  CONCLUSIONS
  This study demonstrated the effectiveness of DCE-MRI with GODP in detecting vascular changes following the administration of bumetanide. Bumetanide has the potential to curtail growth of the tumor vasculature and can be employed in future therapeutic strategies.
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, Wickenden 427, 10900 Euclid Avenue, Mail Stop 7207, Cleveland, Ohio, 44106, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Malamas
authors.forename: Erlei
authors.initials: E
authors.lastname: Jin
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Haaga
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002034:Bumetanide / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003287:Contrast Media / Q000737:chemistry*; D003510:Cyclohexanes / Q000737:chemistry; D003671:DEET / Q000737:chemistry; D019786:Gadolinium DTPA / Q000737:chemistry; D019073:HT29 Cells; D006571:Heterocyclic Compounds / Q000737:chemistry; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009942:Organometallic Compounds / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D003510:Cyclohexanes; D006571:Heterocyclic Compounds; D046911:Macromolecular Substances; D009942:Organometallic Compounds; D002034:Bumetanide; D003671:DEET; C067220:di-tert-butylperoxy-3,3,5-trimethylcyclohexane peroxide; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D019786:Gadolinium DTPA
references.citation: J Magn Reson Imaging. 2011 Dec;34(6):1262-76
references.pmid: 21972053
references.citation: Br Med J. 1972 Jan 22;1(5794):211-3
references.pmid: 4550872
references.citation: Cell Physiol Biochem. 2012;30(1):33-48
references.pmid: 22759954
references.citation: Isr J Chem. 2010 Aug;50(2):220-232
references.pmid: 21331318
references.citation: Nat Med. 2001 Sep;7(9):987-9
references.pmid: 11533692
references.citation: Phys Med Biol. 2012 Jan 21;57(2):R1-33
references.pmid: 22173205
references.citation: Magn Reson Imaging. 1990;8(4):467-81
references.pmid: 2118207
references.citation: Mol Cancer Ther. 2004 May;3(5):647-54
references.pmid: 15141023
references.citation: Am J Physiol Lung Cell Mol Physiol. 2004 Sep;287(3):L510-4
references.pmid: 15155267
references.citation: J Magn Reson Imaging. 1997 Jan-Feb;7(1):68-74
references.pmid: 9039595
references.citation: Mol Pharm. 2010 Feb 1;7(1):41-8
references.pmid: 19958031
references.citation: J Bioenerg Biomembr. 1998 Apr;30(2):161-72
references.pmid: 9672238
references.citation: Cancer Res. 2010 Jul 1;70(13):5597-606
references.pmid: 20570904
references.citation: Drug Resist Updat. 2009 Jun;12(3):74-80
references.pmid: 19394890
references.citation: Semin Cancer Biol. 2008 Oct;18(5):330-7
references.pmid: 18455429
references.citation: Cancer Cell. 2009 Mar 3;15(3):220-31
references.pmid: 19249680
references.citation: Magn Reson Med. 2010 Dec;64(6):1772-80
references.pmid: 20715059
references.citation: J Cell Biol. 1991 Jul;114(2):337-42
references.pmid: 2071675
references.citation: N Engl J Med. 2008 May 8;358(19):2039-49
references.pmid: 18463380
references.citation: Nat Rev Cancer. 2002 Jan;2(1):38-47
references.pmid: 11902584
references.citation: Clin Radiol. 2001 Aug;56(8):607-20
references.pmid: 11467863
references.citation: Eur J Radiol. 2006 Dec;60(3):353-66
references.pmid: 16930905
references.citation: J Pharmacokinet Pharmacodyn. 2013 Jun;40(3):281-300
references.pmid: 23563847
references.citation: Pharm Res. 2009 Sep;26(9):2202-8
references.pmid: 19597972
references.citation: Nature. 2000 Sep 14;407(6801):249-57
references.pmid: 11001068
references.citation: Pharm Res. 2014 Mar;31(3):660-9
references.pmid: 24065590
references.citation: Magn Reson Med. 2008 Dec;60(6):1347-52
references.pmid: 19025902
references.citation: Cancer Metastasis Rev. 2007 Jun;26(2):281-90
references.pmid: 17603752
references.citation: J Clin Oncol. 2005 Feb 20;23(6):1295-311
references.pmid: 15718328
references.citation: J Cereb Blood Flow Metab. 1998 Dec;18(12):1365-77
references.pmid: 9850149
references.citation: Curr Opin Genet Dev. 2010 Feb;20(1):51-6
references.pmid: 19942427
references.citation: Nat Rev Clin Oncol. 2012 Mar;9(3):167-77
references.pmid: 22330689
references.citation: Oral Oncol. 2014 Jan;50(1):19-26
references.pmid: 24269532
references.citation: Eur J Cancer. 2010 May;46(8):1323-32
references.pmid: 20236818
references.citation: Contrast Media Mol Imaging. 2013 May-Jun;8(3):220-8
references.pmid: 23606425
references.citation: Invest Radiol. 2001 Feb;36(2):115-22
references.pmid: 11224760