Cytotoxicity of s-Receptor Ligands Is Associated with Major Changes of Cellular Metabolism and Complete Occupancy of the s-2 Subpopulation

Tumor cells can be selectively killed by application of s-ligands; high concentrations (20–100 mM) are often required, however, because either diffusion barriers must be passed to reach intra-cellular sites or the entire s-receptor population should be occu-pied to induce cell death. We measured receptor occupancies associated with the cytotoxic effect and dose-dependent changes of cellular metabolism in a tumor cell line. Methods: C6 cells (rat glioma) were grown in monolayers and exposed to (1)-pentazocine (s-1 agonist), AC915 (s-1 antagonist), rimcazole (s-1/s-2 antagonist), or haloperidol (s-1/s-2 antagonist). Occu-pancy of s-receptors by the test drugs was measured by study-ing the competition of the test drugs with cellular binding of the ligand 11C-SA4503. Metabolic changes were quantified by mea-suring cellular uptake of 18F-FDG, 18F-FLT, 11C-choline, or 11C-methionine. Cytotoxicity was assessed by cellular morpholog