Early response of sigma-receptor ligands and metabolic PET tracers to 3 forms of chemotherapy:An in vitro study in glioma cells

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 mu mol/L), cisplatin (10 mu mol/L), and 5-fluorouracil (10 mmol/L) were selected to target different aspects of cellular metabolism. Methods: The tracers were 2 extracellular sigma-receptor ligands, F-18-FE-SA5845 (nonsubtype selective) and C-11-SA4503 (sigma-1), the nucleoside 3'-deoxy-3'-F-18-fluorothymidine (F-18-FLT), C-11-choline, C-11-methionine, and F-18-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 sigma-ligands C-11-SA4503 and F-18-FE-SA5845 and the uptake of C-11-choline (normalized for the number of viable cells) were strongly increased. The uptake of F-18-FDG showed little change, and cellular accumulation of F-18-FLT and C-11-methionine was decreased. Uptake of F-18-FLT and C-11-methionine was related to the fraction of cells in S-phase, but not under all conditions: (a) doxorubicin caused a more rapid decline in F-18-FLT uptake than in the S-phase fraction because of depletion of cellular adenosine triphosphate, and (b) cisplatin inhibited the transport of C-11-methionine across the tumor cell membrane. Conclusion: Increased binding of (sigma-ligands and an increased uptake of C-11-choline after chemotherapy may reflect active membrane repair in damaged cells. F-18-FLT and C-11-methionine behaved as proliferation markers. However, the accumulation of F-18-FDG reflected not the proliferation rate but, rather, the number of viable cells per well.