title: TRAIL and doxorubicin combination induces proapoptotic and antiangiogenic effects in soft tissue sarcoma in vivo.
abstract: OBJECTIVE
  Novel therapeutic approaches for complex karyotype soft tissue sarcoma (STS) are crucially needed. Consequently, we assessed the efficacy of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with chemotherapy, on local and metastatic growth of human STS xenografts in vivo.
  
  
  METHODS
  TRAIL was evaluated alone and combined with low-dose doxorubicin in two human STS severe combined immunodeficient mouse xenograft models using fibrosarcoma (HT1080; wild-type p53) and leiomyosarcoma (SKLMS1; mutated p53), testing for effects on local growth, metastasis, and overall survival. Magnetic resonance imaging was used to evaluate local growth and bioluminescence was used to longitudinally assess lung metastases. Tissues were evaluated through immunohistocemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining for treatment effects on tumor cell proliferation, apoptosis, angiogenesis, angiogenic factors, and TRAIL receptor expression. Quantitative real-time polymerase chain reaction (QRTPCR) angiogenesis array was used to assess therapy-induced gene expression changes.
  
  
  RESULTS
  TRAIL/doxorubicin combination induced marked STS local and metastatic growth inhibition in a p53-independent manner. Significantly increased (P < 0.001) host survival was also demonstrable. Combined therapy induced significant apoptosis, decreased tumor cell proliferation, and increased TRAIL receptor (DR4 and DR5) expression in all treated tumors. Moreover, decreased microvessel density was observed, possibly secondary to increased expression of the antiangiogenic factor CXCL10 and decreased proangiogenic interleukin-8 cytokine in response to TRAIL/doxorubicin combination, as was also observed in vitro.
  
  
  CONCLUSIONS
  Given the urgent need for better systemic approaches to STS, clinical trials evaluating TRAIL in combination with low-dose chemotherapy are potentially warranted.
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Suizhao
authors.initials: S
authors.lastname: Wang
authors.forename: Wenhong
authors.initials: W
authors.lastname: Ren
authors.forename: Jeffery
authors.initials: J
authors.lastname: Liu
authors.forename: Guy
authors.initials: G
authors.lastname: Lahat
authors.forename: Keila
authors.initials: K
authors.lastname: Torres
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Lopez
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.forename: Andrea
authors.initials: A
authors.lastname: Hayes-Jordan
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.forename: Jim
authors.initials: J
authors.lastname: Bankson
authors.forename: John D
authors.initials: JD
authors.lastname: Hazle
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D020411:Oligonucleotide Array Sequence Analysis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D054357:Chemokine CXCL10; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin
references.citation: Blood. 2001 Aug 1;98(3):795-804
references.pmid: 11468181
references.citation: Clin Cancer Res. 2009 Mar 15;15(6):2039-47
references.pmid: 19276256
references.citation: Nature. 1997 Apr 3;386(6624):517-21
references.pmid: 9087414
references.citation: Circ Res. 2003 Apr 18;92(7):732-40
references.pmid: 12649264
references.citation: J Clin Oncol. 2009 Jul 1;27(19):3126-32
references.pmid: 19451427
references.citation: Lancet Oncol. 2000 Oct;1:75-85
references.pmid: 11905672
references.citation: Cochrane Database Syst Rev. 2003;(3):CD003293
references.pmid: 12917960
references.citation: Br J Cancer. 2003 Jan 27;88(2):298-306
references.pmid: 12610517
references.citation: Prostate. 2005 Feb 1;62(2):165-86
references.pmid: 15389801
references.citation: Cancer Res. 2009 Feb 1;69(3):1080-8
references.pmid: 19155307
references.citation: Curr Cancer Drug Targets. 2008 Sep;8(6):536-44
references.pmid: 18781899
references.citation: J Orthop Res. 2003 Sep;21(5):949-57
references.pmid: 12919886
references.citation: J Immunol. 2007 Jan 15;178(2):1122-35
references.pmid: 17202376
references.citation: Clin Cancer Res. 2008 Sep 1;14(17):5466-75
references.pmid: 18765538
references.citation: Carcinogenesis. 2006 Sep;27(9):1768-77
references.pmid: 16571651
references.citation: Ann Surg Oncol. 1998 Jan-Feb;5(1):48-53
references.pmid: 9524708
references.citation: J Clin Oncol. 2007 Apr 10;25(11):1390-5
references.pmid: 17416859
references.citation: J Clin Oncol. 2008 Dec 1;26(34):5583-8
references.pmid: 18981463
references.citation: J Clin Oncol. 2004 Nov 15;22(22):4567-74
references.pmid: 15542808
references.citation: Int J Oncol. 2002 May;20(5):949-54
references.pmid: 11956588
references.citation: Eur J Cancer. 2003 Jun;39(9):1318-29
references.pmid: 12763223
references.citation: J Immunol. 2003 Mar 15;170(6):3369-76
references.pmid: 12626597
references.citation: J Clin Invest. 1999 Jul;104(2):155-62
references.pmid: 10411544
references.citation: Nat Rev Cancer. 2005 Nov;5(11):876-85
references.pmid: 16239906
references.citation: Cancer Res. 2001 Mar 15;61(6):2704-12
references.pmid: 11289151
references.citation: Cancer Lett. 2002 Apr 25;178(2):167-74
references.pmid: 11867201
references.citation: Cancer. 2001 Sep 15;92(6):1556-66
references.pmid: 11745235
references.citation: Int J Oncol. 2004 Sep;25(3):677-84
references.pmid: 15289869
references.citation: Cancer. 1999 Jan 15;85(2):389-95
references.pmid: 10023707
references.citation: Nat Rev Cancer. 2008 Oct;8(10):782-98
references.pmid: 18813321
references.citation: Cancer Res. 2008 May 1;68(9):3440-9
references.pmid: 18451172
references.citation: Clin Cancer Res. 2007 Oct 15;13(20):6187-94
references.pmid: 17947486
references.citation: J Orthop Surg (Hong Kong). 2001 Dec;9(2):19-22
references.pmid: 12118126
references.citation: Int J Oncol. 2004 May;24(5):1263-70
references.pmid: 15067350
references.citation: Int J Cancer. 2003 Dec 20;107(6):929-40
references.pmid: 14601052
references.citation: Int J Oncol. 2006 Jan;28(1):127-33
references.pmid: 16327988
references.citation: Mol Cancer Ther. 2006 Dec;5(12):2977-90
references.pmid: 17172403
references.citation: Ann N Y Acad Sci. 2003 Dec;1010:195-9
references.pmid: 15033719
references.citation: Mol Cell. 1999 Oct;4(4):563-71
references.pmid: 10549288
references.citation: Clin Cancer Res. 2003 May;9(5):1648-55
references.pmid: 12738717
references.citation: Neoplasia. 2004 Jul-Aug;6(4):364-73
references.pmid: 15256058
references.citation: N Engl J Med. 2005 Aug 18;353(7):701-11
references.pmid: 16107623
references.citation: Int J Cancer. 2002 Jun 1;99(4):491-504
references.pmid: 11992538
references.citation: Br J Cancer. 2006 May 22;94(10):1428-35
references.pmid: 16622457
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 May;278(5):L1045-50
references.pmid: 10781437
references.citation: Neoplasia. 2001 Nov-Dec;3(6):535-46
references.pmid: 11774036
references.citation: Clin Cancer Res. 2009 May 15;15(10):3472-83
references.pmid: 19417021