In vivo responses of human A375M melanoma to a σ ligand: 18F-FDG PET imaging.
σ-ligands can kill tumor cells. Previously we have shown that a short in vitro incubation of C6 tumor cells with σ-ligands (24 h) results in a dose-dependent increase of cellular (18)F-FDG uptake and that the magnitude of this increase is predictive of subsequent cell death. Here, we aimed to assess whether the σ-ligand rimcazole inhibits growth of A375M melanoma xenografts in nude mice and whether rimcazole treatment changes (18)F-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 (18)F-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, σ-1 and σ-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 (18)F-FDG (measured at day 7). Significant increases of (18)F-FDG uptake at day 14 were observed in the liver and pancreas.


CONCLUSIONS
Rimcazole strongly inhibited the growth of A375M melanoma xenografts. This growth inhibition is accompanied by an early increase of (18)F-FDG uptake in the tumor.
University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen, The Netherlands.
Anna A
AA
Rybczynska
Marco
M
de Bruyn
Nisha K
NK
Ramakrishnan
Johan R
JR
de Jong
Philip H
PH
Elsinga
Wijnand
W
Helfrich
Rudi A J O
RA
Dierckx
Aren
A
van Waarde
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002227:Carbazoles / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D008545:Melanoma / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017480:Receptors, sigma / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D002227:Carbazoles; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D019788:Fluorodeoxyglucose F18; C034931:rimcazole
FDG PET; antitumor effect; melanoma; rimcazole; σ receptors