title: Synergy between vascular targeting agents and antibody-directed therapy.
abstract: OBJECTIVE
  Tumor heterogeneity necessitates the use of combined therapies. We have shown that combining antibody-directed therapy with antivascular agents converts a subcurative to a curative treatment. The purpose of this study was to investigate, by radioluminographic and microscopic techniques, the regional effects of the two complementary therapies.
  
  
  METHODS
  Nude mice bearing colorectal tumors were injected with 125I-labeled anti-carcinoembryonic antigen antibody, and images were obtained for antibody distribution and modeling studies using radioluminography. For therapy studies, the mice were given radioimmunotherapy alone (131I-A5B7 anti-carcinoembryonic antigen antibody), the antivascular agent combretastatin A-4 3-0-phosphate (200 mg/kg), or both. Extra mice were used to study the regional tumor effects of these therapies over time: relevant histochemical procedures were performed on tissue sections to obtain composite digital microscopic images of apoptosis, blood vessels, perfusion, hypoxia, and morphology.
  
  
  RESULTS
  Antibody distribution, modeling, and immunohistochemistry showed how radioimmunotherapy (7.4 MBq/40 microg antibody) effectively treated the outer, well-oxygenated tumor region only. Combretastatin A-4 3-0-phosphate treated the more hypoxic center, and in doing so altered the relationship between tumor parameters.
  
  
  CONCLUSIONS
  The combined complementary therapies produced cures by destroying tumor regions with different pathophysiologies. Relating these regional therapeutic effects to the relevant tumor parameters microscopically allows optimization of therapy and improved translation to clinical trials.
authors.affiliation: Department of Oncology, Cancer Research UK Targeting and Imaging Group, Royal Free and University College Medical School, England, London, UK. r.b.pedley@ucl.ac.uk
authors.forename: R Barbara
authors.initials: RB
authors.lastname: Pedley
authors.forename: Ethaar
authors.initials: E
authors.lastname: El-Emir
authors.forename: Aiden A
authors.initials: AA
authors.lastname: Flynn
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Boxer
authors.forename: Jason
authors.initials: J
authors.lastname: Dearling
authors.forename: James A
authors.initials: JA
authors.lastname: Raleigh
authors.forename: Sally A
authors.initials: SA
authors.lastname: Hill
authors.forename: Sam
authors.initials: S
authors.lastname: Stuart
authors.forename: Reeya
authors.initials: R
authors.lastname: Motha
authors.forename: Richard H J
authors.initials: RH
authors.lastname: Begent
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D003131:Combined Modality Therapy; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology / Q000473:pathology; D009389:Neovascularization, Pathologic; D016499:Radioimmunotherapy; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; D007074:Immunoglobulin G