title: Imaging hypoxia in xenografted and murine tumors with 18F-fluoroazomycin arabinoside: a comparative study involving microPET, autoradiography, PO2-polarography, and fluorescence microscopy.
abstract: OBJECTIVE
  Positron emission tomography (PET) allows noninvasive assessment of tumor hypoxia; however the combination of low resolution and slow tracer clearance from nonhypoxic tissue is problematic. The aim of this study was to examine the in vivo hypoxia selectivity of fluoroazomycin arabinoside ([18F]-FAZA), a promising tracer with improved washout kinetics from oxygenated tissue.
  
  
  METHODS
  Three squamous cell carcinomas and one fibrosarcoma with widely differing spatial patterns of vascularization, hypoxia, and necrosis were grown in mice and evaluated with PET and complementary methods.
  
  
  RESULTS
  Eppendorf electrode measurements consistently demonstrated median PO2 values<1 mm Hg. In accordance with that, PET revealed that all tumors accumulated [18F]-FAZA in excess of reference tissue. Next the two-dimensional spatial distribution of [18F]-FAZA (from autoradiography) was compared with fluorescence images of the same tumor sections showing localization of the hypoxia marker pimonidazole and the perfusion marker Hoechst 33342. Pixel-by-pixel analysis of co-registered images showed a highly significant co-localization between the two hypoxia markers and an inverse correlation (except for the fibrosarcoma) between the distribution of [18F]-FAZA and Hoechst dye. Moreover intratumoral heterogeneity in tracer distribution was clearly visible on autoradiograms, with a [18F]-FAZA concentration approximately six times higher in poorly oxygenated areas than in vascular hot spots.
  
  
  CONCLUSIONS
  The distribution of [18F]-FAZA is consistent with hypoxia as the key driving force for tracer tissue retention in a selection of tumors with widely differing physiology.
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark. morten@oncology.dk
authors.forename: Morten
authors.initials: M
authors.lastname: Busk
authors.forename: Michael R
authors.initials: MR
authors.lastname: Horsman
authors.forename: Steen
authors.initials: S
authors.lastname: Jakobsen
authors.forename: Susanne
authors.initials: S
authors.lastname: Keiding
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van der Kogel
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
mesh_terms: D000818:Animals; D001345:Autoradiography; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000378:metabolism*; D015687:Cell Hypoxia; D005260:Female; D005354:Fibrosarcoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D016867:Immunocompromised Host; D007150:Immunohistochemistry; D051379:Mice; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009593:Nitroimidazoles / Q000493:pharmacokinetics*; D010100:Oxygen / Q000032:analysis / Q000378:metabolism*; D011048:Polarography; D049268:Positron-Emission Tomography / Q000379:methods; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous
chemical_list: D005462:Fluorine Radioisotopes; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C498052:fluoroazomycin arabinoside; C033815:pimonidazole; D010100:Oxygen