title: Vascular disruptive agent OXi4503 and anti-angiogenic agent Sunitinib combination treatment prolong survival of mice with CRC liver metastasis.
abstract: Preclinical research indicate that vascular disrupting agent (VDA) treatment induces extensive tumor death but also a systemic mobilization of bone marrow derived cells including endothelial progenitor cells (EPC) leading to revascularization and renewed growth within the residual tumor. This study investigates if combination of VDA with the anti-angiogenic agent Sunitinib increases the treatment efficacy in a colorectal liver metastases mouse model.
  
  
  
  CBA mice with established liver metastases were given a single dose of OXi4503 at day 16 post tumor induction, a daily dose of Sunitinib starting at day 14 or day 16 post tumor induction or a combination of Sunitinib given daily from day 14 or day 16 post tumor induction in combination with a single dose of OXi4503 at day 16. Treatment was terminated at day 21 post tumor induction and its effects were assessed using stereological and immunohistochemical techniques. Long term effects were assessed in a survival study.
  
  
  
  Combination with long (7 day) Sunitinib treatment lead to liver toxicity but this was ameliorated in the shorter (5 day) treatment without significantly altering the effects on tumor reduction. Combination treatment resulted in significant reduction of viable tumor, reduction in tumor vasculature, reduction in tumor proliferation, increase in tumor apoptosis and prolonged mouse survival compared to control and single arm treatments. Complete tumor eradication was not achieved. Redistribution of E-cadherin and strong up regulation of ZEB1 and Vimentin were observed in the surviving tumor; indicative of epithelial to mesenchymal transition (EMT), a mechanism that could contribute to tumor resistance.
  
  
  
  Combination treatment significantly reduces viable tumor and prolongs animal survival. EMT in the surviving tumor may prevent total tumor eradication and could provide novel targets for a more lasting treatment.
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Lance Townsend Building Level 8, Studley Rd, Heidelberg, VIC, 3084, Australia.
authors.forename: Linh
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Lance Townsend Building Level 8, Studley Rd, Heidelberg, VIC, 3084, Australia. tfifis@unimelb.edu.au.
authors.forename: Theodora
authors.initials: T
authors.lastname: Fifis
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Lance Townsend Building Level 8, Studley Rd, Heidelberg, VIC, 3084, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Christophi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011756:Diphosphates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013267:Stilbenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000077210:Sunitinib; D014746:Vimentin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D015820:Cadherins; C000611838:Cdh1 protein, mouse; D011756:Diphosphates; D007211:Indoles; C465018:Oxi 4503; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013267:Stilbenes; D014746:Vimentin; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000077210:Sunitinib
keywords: Combination therapy; Hypoxia; OXi4503; Sunitinib; Tumor resistance; Vascular disruptive agent