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High-Dose Treatment with ¹⁸⁶Re-HEDP or ¹⁵³Sm-EDTMP Combined with Amifostine in a Rabbit Model

Clinic of Nuclear Medicine, Christian-Albrechts-Universität, Kiel, Germany

The aim of this experimental study was to investigate the myeloprotective potential of amifostine in rabbits receiving high-dose treatment with either ¹⁵³Sm-ethylenediaminetetramethylene phosphonate (EDTMP) or ¹⁸⁶Re-hydroxyethylidene diphosphonate (HEDP) and to check for drug interactions impairing the skeletal uptake of these radiopharmaceuticals by amifostine. Methods: To a total of 24 rabbits, we administered 1,000 MBq of either ¹⁵³Sm-EDTMP (n = 12) or ¹⁸⁶Re-HEDP (n = 12). Six animals of each group received 500 mg amifostine intravenously 10–15 min before injection of the radiopharmaceutical, whereas the other 6 animals served as controls. Up to 8 wk after treatment, blood samples were collected every 3–5 d to measure platelet and leukocyte counts. Furthermore, whole-body images were acquired at 3 min, 3 h, and 24 h after injection of the radiopharmaceutical to quantify the skeletal uptake. Results: For ¹⁸⁶Re-HEDP, the mean decrease in platelets was significantly less in the amifostine group (35.5% ± 2.4%) than in the control group (61.3% ± 5.4%, P < 0.001). Similar results were found for ¹⁵³Sm-EDTMP (36.5% ± 8.3% vs. 52.3% ± 14.0%, P < 0.05). No significant differences in leukocyte counts were found for ¹⁸⁶Re-HEDP (75.3% ± 12.3% in the amifostine group and 72.5% ± 4.1% in the control group, P > 0.05), whereas rabbits treated with ¹⁵³Sm-EDTMP plus amifostine showed a significantly greater decrease in leukocytes (69.2% ± 10.8%) than did the control group (56.6% ± 4.0%, P < 0.05). Bone uptake in percentage of initial total whole-body activity was significantly decreased in animals treated with amifostine compared with the control groups for both ¹⁸⁶Re-HEDP (15.8% ± 3.1% vs. 30.9% ± 1.9%, P < 0.001) and ¹⁵³Sm-EDTMP (31.7% ± 8.9% vs. 44.0% ± 6.5%, P < 0.05). Conclusion: For amifostine, we found a highly significant cytoprotective effect on platelets but no leukoprotective effect. The latter probably relies on the intrinsic myelotoxicity of high-dose amifostine, which seemed to potentiate the leukodepression of the radiopharmaceuticals. The lower bone uptake in amifostine-treated animals may be caused by the chemical structure of amifostine, which is a potentially complex-forming compound that may be able to displace bisphosphonates from the rhenium– and samarium–bisphosphonate complexes, resulting in altered biodistribution patterns.

Key Words: amifostine • myeloprotection • ¹⁸⁶Re-hydroxyethylidene diphosphonate • ¹⁵³Sm-ethylenediaminetetramethylene phosphonate • skeletal uptake