title: Tumor dynamics in response to antiangiogenic therapy with oral metronomic topotecan and pazopanib in neuroblastoma xenografts.
abstract: Metronomic chemotherapy, combined with targeted antiangiogenic drugs, has demonstrated significant anticancer efficacy in various studies. Though, tumors do acquire resistance. Here, we have investigated the effect of prolonged therapy with oral metronomic topotecan and pazopanib on tumor behavior in a neuroblastoma mouse xenograft model. SK-N-BE(2) xenograft-bearing mice were treated with either of the following regimens (daily, orally): vehicle (control), 150 mg/kg pazopanib, 1.0 mg/kg topotecan, and combination of topotecan and pazopanib. Planned durations of treatment for each regimen were 28, 56, and 80 days or until the end point, after which animals were sacrificed. We found that only combination-treated animals survived until 80 days. Combination halted tumor growth for up to 50 days, after which gradual growth was observed. Unlike single agents, all three durations of combination significantly lowered microvessel densities compared to the control. However, the tumors treated with the combination for 56 and 80 days had higher pericyte coverage compared to control and those treated for 28 days. The proliferative and mitotic indices of combination-treated tumors were higher after 28 days of treatment and comparable after 56 days and 80 days of treatment compared to control. Immunohistochemistry, Western blot, and real-time polymerase chain reaction revealed that combination treatment increased the hypoxia and angiogenic expression. Immunohistochemistry for Glut-1 and hexokinase II expression revealed a metabolic switch toward elevated glycolysis in the combination-treated tumors. We conclude that prolonged combination therapy with metronomic topotecan and pazopanib demonstrates sustained antiangiogenic activity but also incurs resistance potentially mediated by elevated glycolysis.
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada ; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.forename: Reza Bayat
authors.initials: RB
authors.lastname: Mokhtari
authors.forename: Indhira Dias
authors.initials: ID
authors.lastname: Oliveira
authors.forename: Syed
authors.initials: S
authors.lastname: Islam
authors.forename: Silvia Regina Caminada
authors.initials: SR
authors.lastname: Toledo
authors.forename: Herman
authors.initials: H
authors.lastname: Yeger
authors.forename: Sylvain
authors.initials: S
authors.lastname: Baruchel
references.citation: Mol Cancer Ther. 2010 Jul;9(7):2068-78
references.pmid: 20606044
references.citation: Cancer Invest. 2006 Jun-Jul;24(4):432-43
references.pmid: 16777697
references.citation: J Clin Oncol. 2010 May 20;28(15):2625-34
references.pmid: 20404250
references.citation: Neuro Oncol. 2007 Jul;9(3):354-63
references.pmid: 17452651
references.citation: Nat Rev Drug Discov. 2012 Feb 03;11(3):215-33
references.pmid: 22301798
references.citation: J Pediatr Surg. 2013 Jan;48(1):39-46
references.pmid: 23331791
references.citation: Mol Cancer Ther. 2010 Apr;9(4):996-1006
references.pmid: 20371722
references.citation: Cancer Res. 2010 Dec 15;70(24):10351-61
references.pmid: 20961996
references.citation: J Pediatr Surg. 2012 Jul;47(7):1323-30
references.pmid: 22813791
references.citation: Angiogenesis. 2013 Apr;16(2):373-86
references.pmid: 23143659
references.citation: Neoplasia. 2011 Jan;13(1):40-8
references.pmid: 21245939
references.citation: J Clin Oncol. 2008 Jan 1;26(1):76-82
references.pmid: 18165643
references.citation: Clin Cancer Res. 2001 Apr;7(4):928-34
references.pmid: 11309343
references.citation: Cell Cycle. 2009 Oct 15;8(20):3355-64
references.pmid: 19770592
references.citation: Cancer Res. 2005 Jun 1;65(11):4775-81
references.pmid: 15930297
references.citation: Cancer Lett. 2013 Apr 28;330(2):241-9
references.pmid: 23228633
references.citation: Genes Cancer. 2010 Jan;1(1):12-25
references.pmid: 21779425
references.citation: J Neurochem. 2010 May;113(4):819-25
references.pmid: 20180881
references.citation: Br J Cancer. 2003 Apr 22;88(8):1310-7
references.pmid: 12698201
references.citation: J Proteomics. 2010 May 7;73(7):1342-54
references.pmid: 20219715
references.citation: BMC Cancer. 2011 May 12;11:167
references.pmid: 21569415
references.citation: Clin Breast Cancer. 2012 Jun;12(3):207-14
references.pmid: 22520733
references.citation: J Clin Invest. 2000 Apr;105(8):R15-24
references.pmid: 10772661
references.citation: Nat Rev Cancer. 2008 Aug;8(8):592-603
references.pmid: 18650835
references.citation: Pediatr Blood Cancer. 2013 Mar;60(3):409-14
references.pmid: 23065953
references.citation: Oncogene. 2006 Aug 7;25(34):4777-86
references.pmid: 16892090
references.citation: Nat Rev Clin Oncol. 2012 Apr 24;9(7):378-90
references.pmid: 22525710
references.citation: Radiat Oncol. 2011 May 30;6:56
references.pmid: 21624128
references.citation: J Neurooncol. 2011 Jun;103(2):371-9
references.pmid: 20853132
references.citation: Br J Cancer. 2009 Dec 15;101(12):1986-94
references.pmid: 19920819
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Science. 2002 Feb 22;295(5559):1526-8
references.pmid: 11859195
references.citation: Carcinogenesis. 2004 Dec;25(12):2325-35
references.pmid: 15347600
references.citation: Lab Invest. 2012 Jul;92(7):952-66
references.pmid: 22546866
references.citation: Jpn J Cancer Res. 2002 Oct;93(10):1123-8
references.pmid: 12417042
references.citation: J Pediatr Hematol Oncol. 2006 Nov;28(11):720-8
references.pmid: 17114958
references.citation: Transl Oncol. 2011 Aug;4(4):203-11
references.pmid: 21804915
references.citation: BMC Cancer. 2011 Oct 20;11:453
references.pmid: 22014006
references.citation: Gut. 2013 Feb;62(2):259-71
references.pmid: 22543158
references.citation: Cancer Metab. 2013 Jan 23;1(1):2
references.pmid: 24280485
references.citation: Biosci Biotechnol Biochem. 2010;74(6):1181-7
references.pmid: 20530905
references.citation: Prostate Cancer Prostatic Dis. 2012 Mar;15(1):15-27
references.pmid: 22083267
references.citation: BMC Cancer. 2009 Jul 20;9:241
references.pmid: 19619276
references.citation: Nat Rev Clin Oncol. 2010 Aug;7(8):455-65
references.pmid: 20531380
references.citation: Cancer Cell Int. 2011 Feb 14;11:3
references.pmid: 21320311
references.citation: J Clin Invest. 2003 Oct;112(8):1142-51
references.pmid: 14561699
references.citation: J Clin Oncol. 2008 Oct 20;26(30):4899-905
references.pmid: 18794539
references.citation: Transl Oncol. 2013 Feb;6(1):1-9
references.pmid: 23418611
references.citation: Mol Cancer Ther. 2010 Apr;9(4):985-95
references.pmid: 20371710
references.citation: BMC Cancer. 2011 Feb 08;11:58
references.pmid: 21299907
references.citation: BMC Cancer. 2009 Dec 16;9:444
references.pmid: 20015387
references.citation: Oncol Rep. 2012 Aug;28(2):439-45
references.pmid: 22641525
references.citation: Cancer Immunol Immunother. 2009 Feb;58(2):259-70
references.pmid: 18594817
references.citation: Clin Adv Hematol Oncol. 2011 Feb;9(2):101-10
references.pmid: 22173604
references.citation: Clin Cancer Res. 2011 Sep 1;17(17):5656-67
references.pmid: 21788355
references.citation: Nat Rev Cancer. 2004 Jun;4(6):423-36
references.pmid: 15170445
references.citation: Nat Rev Clin Oncol. 2009 Jun;6(6):327-38
references.pmid: 19483739
references.citation: Expert Opin Investig Drugs. 2010 Jul;19(7):859-74
references.pmid: 20470190
references.citation: Mol Cancer Ther. 2008 Jul;7(7):1974-84
references.pmid: 18645007
references.citation: PLoS One. 2009;4(4):e5123
references.pmid: 19352490