title: Differential mechanisms associated with vascular disrupting action of electrochemotherapy: intravital microscopy on the level of single normal and tumor blood vessels.
abstract: Electropermeabilization/electroporation (EP) provides a tool for the introduction of molecules into cells and tissues. In electrochemotherapy (ECT), cytotoxic drugs are introduced into cells in tumors, and nucleic acids are introduced into cells in gene electrotransfer. The normal and tumor tissue blood flow modifying effects of EP and the vascular disrupting effect of ECT in tumors have already been determined. However, differential effects between normal vs. tumor vessels, to ensure safety in the clinical application of ECT, have not been determined yet. Therefore, the aim of our study was to determine the effects of EP and ECT with bleomycin on the HT-29 human colon carcinoma tumor model and its surrounding blood vessels. The response of blood vessels to EP and ECT was monitored in real time, directly at the single blood vessel level, by in vivo optical imaging in a dorsal window chamber in SCID mice with 70 kDa fluorescently labeled dextrans. The response of tumor blood vessels to EP and ECT started to differ within the first hour. Both therapies induced a vascular lock, decreased functional vascular density (FVD) and increased the diameter of functional blood vessels within the tumor. The effects were more pronounced for ECT, which destroyed the tumor blood vessels within 24 h. Although the vasculature surrounding the tumor was affected by EP and ECT, it remained functional. The study confirms the current model of tumor blood flow modifying effects of EP and provides conclusive evidence that ECT is a vascular disrupting therapy with a specific effect on the tumor blood vessels.
authors.affiliation: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors.forename: Bostjan
authors.initials: B
authors.lastname: Markelc
authors.forename: Gregor
authors.initials: G
authors.lastname: Sersa
authors.forename: Maja
authors.initials: M
authors.lastname: Cemazar
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000494:pharmacology / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003911:Dextrans / Q000378:metabolism; D053672:Electrochemotherapy; D018274:Electroporation; D005260:Female; D019073:HT29 Cells; D006801:Humans; D017879:Isothiocyanates / Q000378:metabolism; D051379:Mice; D008853:Microscopy
chemical_list: D003911:Dextrans; D017879:Isothiocyanates; D001761:Bleomycin; C037152:isothiocyanic acid
references.citation: Anticancer Drugs. 2000 Mar;11(3):201-8
references.pmid: 10831279
references.citation: Mol Cancer Ther. 2006 Dec;5(12):3145-52
references.pmid: 17172418
references.citation: Cancer Res. 2012 Mar 15;72(6):1336-41
references.pmid: 22282658
references.citation: Br J Cancer. 2008 Jan 29;98(2):388-98
references.pmid: 18182988
references.citation: Curr Gene Ther. 2010 Aug;10(4):281-6
references.pmid: 20504275
references.citation: Br J Cancer. 2002 Oct 21;87(9):1047-54
references.pmid: 12434299
references.citation: Exp Cell Res. 1988 Mar;175(1):15-25
references.pmid: 3345798
references.citation: J Neurosurg. 2011 Mar;114(3):681-8
references.pmid: 20560725
references.citation: EMBO J. 1982;1(7):841-5
references.pmid: 6329708
references.citation: Radiol Oncol. 2010 Mar;44(1):34-41
references.pmid: 22933889
references.citation: Curr Opin Immunol. 2011 Jun;23(3):421-9
references.pmid: 21530212
references.citation: Nat Rev Cancer. 2005 Jun;5(6):423-35
references.pmid: 15928673
references.citation: Curr Pharm Des. 2006;12(29):3817-25
references.pmid: 17073680
references.citation: Bioelectrochemistry. 2007 May;70(2):287-95
references.pmid: 17140860
references.citation: Semin Cancer Biol. 2003 Apr;13(2):159-67
references.pmid: 12654259
references.citation: Int J Pharm. 2012 Feb 14;423(1):3-6
references.pmid: 21996516
references.citation: Melanoma Res. 2000 Dec;10(6):585-9
references.pmid: 11198481
references.citation: PLoS One. 2009;4(3):e4757
references.pmid: 19270746
references.citation: Radiol Oncol. 2012 Dec;46(4):302-11
references.pmid: 23412658
references.citation: Acta Oncol. 2012 Jul;51(6):713-21
references.pmid: 22731832
references.citation: J Natl Cancer Inst. 2006 Mar 1;98(5):335-44
references.pmid: 16507830
references.citation: Nat Rev Cancer. 2002 Apr;2(4):266-76
references.pmid: 12001988
references.citation: PLoS One. 2007 Nov 07;2(11):e1135
references.pmid: 17989772
references.citation: Nat Protoc. 2011 Aug 18;6(9):1355-66
references.pmid: 21886101
references.citation: Eur J Cancer. 1999 Apr;35(4):672-7
references.pmid: 10492645
references.citation: Biochim Biophys Acta. 2002 Jan 15;1569(1-3):51-8
references.pmid: 11853957
references.citation: Methods Mol Med. 2003;85:65-78
references.pmid: 12710198
references.citation: Cancer Res. 2001 May 15;61(10):4266-71
references.pmid: 11358854
references.citation: Tumori. 2009 May-Jun;95(3):398-402
references.pmid: 19688986
references.citation: Eur J Surg Oncol. 2008 Feb;34(2):232-40
references.pmid: 17614247
references.citation: J Membr Biol. 2012 Sep;245(9):545-54
references.pmid: 22644389
references.citation: Anticancer Res. 1999 Sep-Oct;19(5B):4017-22
references.pmid: 10628347
references.citation: Radiol Oncol. 2012 Dec;46(4):271-8
references.pmid: 23412694
references.citation: Histochem Cell Biol. 2008 Dec;130(6):1147-54
references.pmid: 18987875
references.citation: Curr Gene Ther. 2010 Aug;10(4):312-7
references.pmid: 20557286
references.citation: Expert Rev Anticancer Ther. 2010 May;10(5):729-46
references.pmid: 20470005
references.citation: J Control Release. 2012 Nov 10;163(3):396-403
references.pmid: 23017380
references.citation: Mol Biotechnol. 2009 Oct;43(2):167-76
references.pmid: 19562526
references.citation: Cancer Treat Rev. 2011 Feb;37(1):63-74
references.pmid: 20570444
references.citation: Technol Cancer Res Treat. 2007 Aug;6(4):307-12
references.pmid: 17668938
references.citation: Technol Cancer Res Treat. 2007 Aug;6(4):295-300
references.pmid: 17668936
references.citation: Br J Cancer. 2001 Feb;84(4):565-70
references.pmid: 11207055
references.citation: PLoS One. 2012;7(12):e52713
references.pmid: 23300747
references.citation: Toxicol Mech Methods. 2012 Jun;22(5):383-96
references.pmid: 22409285
references.citation: Br J Cancer. 2004 Feb 23;90(4):906-10
references.pmid: 14970872
references.citation: Br J Cancer. 1998 Jun;77(12):2104-11
references.pmid: 9649121
references.citation: Curr Gene Ther. 2010 Aug;10(4):300-11
references.pmid: 20560875
references.citation: Spectrochim Acta A Mol Biomol Spectrosc. 2004 May;60(6):1379-85
references.pmid: 15134738
references.citation: Cancer Res. 2011 Jun 1;71(11):3753-62
references.pmid: 21507935
references.citation: Technol Cancer Res Treat. 2011 Oct;10(5):475-85
references.pmid: 21895032
references.citation: Eur J Cancer. 1991;27(1):68-72
references.pmid: 1707289