Analysis of the regional uptake of radiolabeled deoxyglucose analogs in human tumor xenografts.
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.
Dearling
Jason L J
JL
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
Flynn
Aiden A
AA
Sutcliffe-Goulden
Julie
J
Petrie
Ingrid A
IA
Boden
Robert
R
Green
Alan J
AJ
Boxer
Geoffrey M
GM
Begent
Richard H J
RH
Pedley
R Barbara
RB
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
D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D003847:Deoxyglucose; D005947:Glucose