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This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Rybczynska, A. Articles by Van Waarde, A. PubMed Articles by Rybczynska, A. Articles by Van Waarde, A.

High receptor occupancy is required for cytotoxicity of sigma antagonists

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

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Objectives: Cytotoxicity of sigma ligands has been reported in several publications. Such drugs must be administered in 20 to 100 µM concentrations. The reason for this requirement is unknown. Large amounts of drug may be required because biomembranes limit drug access to intracellular sites, but also because a large fraction of the receptor population must be occupied for the cytotoxic effect. We tested which sigma receptor occupancy is needed for cytotoxicity in tumor cells.

Methods: C6 cells (rat glioma) were grown in monolayers and exposed to the following drugs: (1) (+)-Pentazocine (sigma-1 agonist); (2) AC915 (sigma-1 antagonist); (3) Rimcazole (sigma-1/sigma-2 antagonist) and (4) Haloperidol (sigma-1/sigma-2 antagonist). Occupancy of sigma receptors by the test drugs was measured by studying their competition with cellular binding of the ligand 11C-SA4503. Cytotoxic effects were assessed by observation of cellular morphology and by cell counting after 24h.

Results: Dose-dependent inhibition of 11C-SA4503 binding by the test drugs was observed, with IC50 values of 6.5 µM (pentazocine), 7.4 µM (AC915), 0.4 µM (rimcazole) and 0.3 µM (haloperidol), respectively. Rounding and detachment of the cells occurred at drug concentrations 100µM (AC915), 20µM (rimcazole) and 10µM (haloperidol), respectively, whereas pentazocine had little effect even at 100µM.

Conclusions: Since cytotoxicity was only observed at concentrations > 10 times greater than IC50-values for inhibition of cellular 11C-SA4503 binding, high (> 90%) receptor occupancy is required for rapid cell killing by sigma antagonists. In C6 cells, 96% occupancy of sigma receptors by an agonist (pentazocine) appeared to be not cytotoxic.

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Rybczynska, A. Articles by Van Waarde, A. PubMed Articles by Rybczynska, A. Articles by Van Waarde, A.