In Vivo Responses of Human A375M Melanoma to a sigma Ligand: F-18-FDG PET Imaging

sigma-ligands can kill tumor cells. Previously we have shown that a short in vitro incubation of C6 tumor cells with sigma-ligands (24 h) results in a dose-dependent increase of cellular F-18-FDG uptake and that the magnitude of this increase is predictive of subsequent cell death. Here, we aimed to assess whether the sigma-ligand rimcazole inhibits growth of A375M melanoma xenografts in nude mice and whether rimcazole treatment changes F-18-FDG uptake in vivo. Methods: Athymic mice were inoculated with A375M melanoma cells. After 2 wk, tumors had reached a size of 41 +/- 6 mm(3). We then started a 14-d treatment schedule with daily drug dosing. Control animals were injected with water and treated animals with rimcazole (26 mg/kg) in water. Three small-animal PET scans with F-18-FDG were obtained: on days 0, 7, and 14 of treatment. After the last scan, animals were terminated, and a biodistribution study was performed. Results: Rimcazole treatment resulted in a greater than 4-fold reduction of tumor weight in comparison to controls at day 14 (100 +/- 26 vs. 436 +/- 117 mg, respectively, P <0.03). Treatment did not affect the levels of (nonradioactive) glucose in blood, sigma-1 and sigma-2 receptor expression in the tumor, animal weight, behavior, or appearance. Antitumor activity of rimcazole was accompanied by a transient increase of the tumor uptake of F-18-FDG (measured at day 7). Significant increases of F-18-FDG uptake at day 14 were observed in the liver and pancreas. Conclusion: Rimcazole strongly inhibited the growth of A375M melanoma xenografts. This growth inhibition is accompanied by an early increase of F-18-FDG uptake in the tumor.