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

¹ Nuclear Medicine and Molecular Imaging, University of Groningen Medical Center, 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, Nuclear Medicine and Molecular Imaging, University of Groningen Medical Center, Hanzeplein 1, 9700 RB Groningen, The Netherlands. E-mail: a.van.waarde{at}ngmb.umcg.nl

Tumor cells can be selectively killed by application of -ligands; high concentrations (20–100 µM) are often required, however, because either diffusion barriers must be passed to reach intracellular sites or the entire -receptor population should be occupied 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 (+)-pentazocine (-1 agonist), AC915 (-1 antagonist), rimcazole (-1/-2 antagonist), or haloperidol (-1/-2 antagonist). Occupancy of -receptors by the test drugs was measured by studying the competition of the test drugs with cellular binding of the ligand ¹¹C-SA4503. Metabolic changes were quantified by measuring cellular uptake of ¹⁸F-FDG, ¹⁸F-FLT, ¹¹C-choline, or ¹¹C-methionine. Cytotoxicity was assessed by cellular morphology observation and cell counting after 24 h. Results: IC₅₀ values (drug concentrations resulting in 50% occupancy of the available binding sites) of the test drugs for inhibition of cellular ¹¹C-SA4503 binding were 6.5, 7.4, 0.36, and 0.27 µM for (+)-pentazocine, AC915, rimcazole, and haloperidol, respectively. EC₅₀ values (dose required for a 50% reduction of cell number after 24 h) were 710, 819, 31, and 58 µM, for pentazocine, AC915, rimcazole, and haloperidol, respectively. Cytotoxic doses of -ligands were generally associated with increased uptake of ¹⁸F-FDG, decreased uptake of ¹⁸F-FLT and ¹¹C-choline, and little change in ¹¹C-methionine uptake per viable cell. Conclusion: IC₅₀ values of the test drugs reflect their in vitro affinities to -2 rather than to -1 receptors. Because cytotoxicity occurred at concentrations 2 orders of magnitude higher than IC₅₀ values for inhibition of cellular ¹¹C-SA4503 binding, high (99%) occupancy of -2 receptors is associated with loss of cell viability. ¹⁸F-FLT, ¹¹C-choline, and ¹⁸F-FDG responded most strongly to drug treatment and showed changes corresponding to the cytotoxicity of the test compounds.

Key Words: PET • -receptor occupancy • cellular proliferation • glioma cells • ¹⁸F-FLT • ¹⁸F-FDG • ¹¹C-choline • ¹¹C-methionine

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JNM 2008 49: 11A-12A. [Full Text]