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Early Response of -Receptor Ligands and Metabolic PET Tracers to 3 Forms of Chemotherapy: An In Vitro Study in Glioma Cells

¹ Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; and ² Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

Correspondence: For correspondence or reprints contact: Aren van Waarde, PhD, Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: a.van.waarde{at}pet.umcg.nl

The significant presence of nontumor cell populations within tumors can complicate the assessment of in vivo tumor metabolism during therapy. To more clearly define the impact of cytotoxic agents, we compared early changes in the uptake of 6 PET tracers in cultured glioma cells. Doxorubicin (1 µmol/L), cisplatin (10 µmol/L), and 5-fluorouracil (10 mmol/L) were selected to target different aspects of cellular metabolism. Methods: The tracers were 2 extracellular -receptor ligands, ¹⁸F-FE-SA5845 (nonsubtype selective) and ¹¹C-SA4503 (-1), the nucleoside 3'-deoxy-3'-¹⁸F-fluorothymidine (¹⁸F-FLT), ¹¹C-choline, ¹¹C-methionine, and ¹⁸F-FDG. C6 glioma cells were grown as monolayers and exposed to cytotoxic agents at concentrations at least 1 order of magnitude higher than the concentration for 50% growth inhibition of this cell line. Effects on cellular parameters were measured after 0, 1, 2, 3, 4, and 24 h. Results: All treatments resulted in a decline in cell numbers within 24 h. The binding of the -ligands ¹¹C-SA4503 and ¹⁸F-FE-SA5845 and the uptake of ¹¹C-choline (normalized for the number of viable cells) were strongly increased. The uptake of ¹⁸F-FDG showed little change, and cellular accumulation of ¹⁸F-FLT and ¹¹C-methionine was decreased. Uptake of ¹⁸F-FLT and ¹¹C-methionine was related to the fraction of cells in S-phase, but not under all conditions: (a) doxorubicin caused a more rapid decline in ¹⁸F-FLT uptake than in the S-phase fraction because of depletion of cellular adenosine triphosphate, and (b) cisplatin inhibited the transport of ¹¹C-methionine across the tumor cell membrane. Conclusion: Increased binding of -ligands and an increased uptake of ¹¹C-choline after chemotherapy may reflect active membrane repair in damaged cells. ¹⁸F-FLT and ¹¹C-methionine behaved as proliferation markers. However, the accumulation of ¹⁸F-FDG reflected not the proliferation rate but, rather, the number of viable cells per well.

Key Words: -receptor ligands • 3'-deoxy-3'-fluorothymidine • doxorubicin • cisplatin • 5-fluorouracil

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