title: Analysis of the regional uptake of radiolabeled deoxyglucose analogs in human tumor xenografts.
abstract: It has been shown in vitro that the cell uptake of (18)F-FDG, a tracer of glucose metabolism, increases under hypoxia. This is consistent with increased glycolytic metabolism. We have previously shown that in ischemic heart ex vivo the rates of uptake of (18)F-FDG and 2-(14)C-deoxy-D-glucose ((14)C-2DG) are both reduced. In this study, we investigated this effect in tumors by comparing the microdistribution of (18)F-FDG and (14)C-2DG in hypoxic and normoxic regions.
  
  
  METHODS
  Mice (MF1) bearing LS174T human tumor xenografts were injected with premixed (18)F-FDG (100 MBq), (14)C-2DG (0.37 MBq), and pimonidazole hydrochloride (60 mg/kg). After 30, 60, and 120 min, tissues (n = 4) were taken and counted for whole-body biodistribution. Tumors were frozen, sectioned, and exposed to phosphor image plates to obtain a quantitative digital image of radionuclide distribution. Sections were then stained to reveal tumor pathophysiology: Hematoxylin and eosin staining demonstrated viable and necrotic regions, and immunohistochemical staining detected pimonidazole metabolism in hypoxic cells. The images of radionuclide microdistribution and histology were then coregistered and analyzed to assess radionuclide trapping throughout the tumor on a pixel-by-pixel basis. The Pearson correlation coefficients between the 2 radionuclides were calculated. The relative amounts of nuclide were then analyzed in viable and necrotic regions and in normoxic and hypoxic regions.
  
  
  RESULTS
  Whole-body biodistributions for the 2 radiotracers were similar. A high Pearson correlation coefficient was obtained for the 2 radionuclides throughout the tumors (r = 0.85 +/- 0.10, P < 0.0001), indicating a highly similar microdistribution. When the tumors were divided into viable and necrotic regions, the ratio of mean counts per pixel was 1.96 (P < 0.0001), whereas for hypoxic versus normoxic regions it was 1.26 (P < 0.0001). There was no significant difference in selectivity for hypoxia between the 2 radiotracers (P = 0.86).
  
  
  CONCLUSIONS
  The tumor microdistribution of deoxyglucose in viable, hypoxic, and necrotic regions show that there was little change in the microdistribution of deoxyglucose throughout this time course. This study extends previous in vitro work and confirms the selectivity of deoxyglucose for viable cells over necrotic regions and for hypoxic cells over normoxic regions in vivo.
authors.affiliation: Cancer Research UK Targeting and Imaging Group, Academic Department of Oncology, Royal Free and University College Medical School, Royal Free Campus, University College London, Hampstead, London, United Kingdom. j.dearling@ucl.ac.uk
authors.forename: Jason L J
authors.initials: JL
authors.lastname: Dearling
authors.forename: Aiden A
authors.initials: AA
authors.lastname: Flynn
authors.forename: Julie
authors.initials: J
authors.lastname: Sutcliffe-Goulden
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Petrie
authors.forename: Robert
authors.initials: R
authors.lastname: Boden
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Green
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Boxer
authors.forename: Richard H J
authors.initials: RH
authors.lastname: Begent
authors.forename: R Barbara
authors.initials: RB
authors.lastname: Pedley
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002250:Carbon Radioisotopes; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D003847:Deoxyglucose / Q000493:pharmacokinetics*; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014915:Whole-Body Counting
chemical_list: D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D003847:Deoxyglucose; D005947:Glucose