Pharmacologic activation of tumor hypoxia: a means to increase tumor 2-deoxy-2-[18F]fluoro-D-glucose uptake?
Tumor hypoxia and tumor metabolism are linked through the activation of metabolic genes following hypoxia-inducible factor 1 (HIF-1) activation. This raises the question of whether this relationship can be exploited to improve 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography ([(18)F]FDG-PET). To do this, [(18)F]FDG uptake was investigated after chemical induction of hypoxia and chemical activation of HIF-1 in an in vitro and an in vivo model of a human colorectal carcinoma. [(18)F]FDG uptake, HIF-1α protein levels, and messenger ribonucleic acid expression of glucose transporter 1 (GLUT1), hexokinase 2, HIF-1α, and carbonic anhydrase IX (CA IX) were determined in HT29 cells after treatment with 200 μM CoCl(2) and 500 μM dimethyloxalylglycine (DMOG). In an HT29 xenograft, the distribution of endogenous and exogenous markers of hypoxia was investigated using immunohistochemistry, and tumor [(18)F]FDG uptake was determined after treatment with a single dose of 5 mg/kg hydralazine and 8 mg DMOG. Treatment of HT29 cells with CoCl(2) and DMOG induced functional HIF-1 and resulted in increased [(18)F]FDG uptake. In an HT29 xenograft, a similar spatial distribution of pimonidazole, CA IX, and GLUT1 was found, and treatment with DMOG resulted in significant increases in maximum and mean standardized uptake values using [(18)F]FDG-PET. Chemical activation of HIF-1 can increase in vitro and in vivo [(18)F]FDG uptake. Imaging after pharmacologic HIF-1 activation might increase tumor [(18)F]FDG uptake when using [(18)F]FDG-PET.
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Gilles
G
Mees
Rudi
R
Dierckx
Christel
C
Vangestel
Debby
D
Laukens
Nancy
N
Van Damme
Christophe
C
Van de Wiele
D000600:Amino Acids, Dicarboxylic; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D015687:Cell Hypoxia / Q000502:physiology*; D003035:Cobalt; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D019073:HT29 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods; D009374:Neoplasms, Experimental / Q000737:chemistry / Q000000981:diagnostic imaging / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000600:Amino Acids, Dicarboxylic; D051793:Hypoxia-Inducible Factor 1; D019788:Fluorodeoxyglucose F18; D003035:Cobalt; C018021:cobaltous chloride; C040947:oxalylglycine