Glucose transporter protein-independent tumor cell accumulation of fluorine-18-AFDG, a lipophilic fluorine-18-FDG analog.

Abstract

UNLABELLED:

Fluorine-18-fluorodeoxyglucose (FDG) is used clinically for tumor diagnosis, but its mechanism of accumulation in tumor cells is complicated because two factors, glucose transporter protein (GLUT) and hexokinase, govern [18F]FDG uptake directly. We selected a lipophilic [18F]FDG analog, 1,3,4,6-tetra-acetyl-2-[18F]-2-deoxy-D-glucose ([18F]AFDG), to regulate the effects of hexokinase and evaluated its characteristics in an in vitro cell culture system.

METHODS:

Fluorine-18-AFDG was synthesized by the method used to produce [18F]FDG, as an intermediate of [18F]FDG. Fluorine-18-AFDG uptake study was performed with LS180 tumor cells, and its metabolites were also investigated by thin-layer chromatography. To evaluate the relationship between [18F]AFDG and GLUT, we also examined [18F]AFDG uptake in the presence of cytochalasin B or with increased medium glucose concentration. The effects of lowered temperature (4 degrees C) on [18F]AFDG uptake were also investigated.

RESULTS:

Fluorine-18-AFDG (lipophilicity: octanol/water = 3.5) uptake was 3.3-fold higher than that of [18F]FDG. Metabolic analysis showed that [18F]AFDG was extremely stable in the incubation medium but was quickly hydrolyzed and metabolized to 2-fluoro-[18F]-2-deoxy-D-glucose-6-phosphate ([18F]FDG-6P) in tumor cells. Fluorine-18-FDG-6P accounted for approximately 45% of the total radioactivity after a 60-min incubation of [18F]AFDG. Incubation with 50 microM cytochalasin B did not affect [18F]AFDG uptake. In medium with double the control glucose level, [18F]FDG uptake was decreased by about 50%, but [18F]AFDG uptake was not affected. Fluorine-18-AFDG uptake and [18F]FDG-6P production did not show saturation and increased linearly with addition of a 10-fold higher concentration of [18F]AFDG. Lowered incubation temperature caused decreased [18F]AFDG uptake due to reduced [18F]FDG-6P production.

CONCLUSION:

Fluorine-18-AFDG rapidly penetrated the cell membrane as a result of its high lipophilicity and was metabolized to [18F]FDG-6P within cells. Fluorine-18-AFDG was thus characterized as "GLUT-independent [18F]FDG."

• Authors: A Waki, Y Fujibayashi, Y Magata, A Yokoyama, N Sadato, T Tsuchida, Y Ishii, Y Yonekura
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 39 Issue 2 Pg. 245-50 (Feb 1998) ISSN: 0161-5505 [Print] United States
• PMID: 9476929 (Publication Type: Journal Article)

Chemical References

• 1,3,4,6-tetraacetyl-2-fluoro-2-deoxyglucose
• Monosaccharide Transport Proteins
• Fluorodeoxyglucose F18
• Cytochalasin B
• Deoxyglucose
• Glucose

Topics

• Cytochalasin B (pharmacology)
• Deoxyglucose (analogs & derivatives, pharmacokinetics)
• Fluorodeoxyglucose F18 (analogs & derivatives, pharmacokinetics)
• Glucose (metabolism)
• Humans
• Monosaccharide Transport Proteins (antagonists & inhibitors, metabolism)
• Tumor Cells, Cultured (metabolism)