Pharmacologic Activation of Tumor Hypoxia:A Means to Increase Tumor 2-Deoxy-2-[F-18]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-[F-18]fluoro-D-glucose positron emission tomography ([F-18]FDG-PET). To do this, [F-18]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. [F-18]FDG uptake, HIF-1 alpha protein levels, and messenger ribonucleic acid expression of glucose transporter 1 (GLUT1), hexokinase 2, HIF-1 alpha, and carbonic anhydrase IX (CA IX) were determined in HT29 cells after treatment with 200 mu M CoCl2 and 500 mu M dimethyloxalylglycine (DMOG). In an HT29 xenograft, the distribution of endogenous and exogenous markers of hypoxia was investigated using immunohistochemistry, and tumor [F-18]FDG uptake was determined after treatment with a single dose of 5 mg/kg hydralazine and 8 mg DMOG. Treatment of HT29 cells with CoCl2 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.