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Re-assessing gallium-67 as a therapeutic radionuclide ☆

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Despite its desirable half-life and low energy Auger electrons that travel further than for other radionuclides, 67Ga has been neglected as a therapeutic radionuclide. Here, 67Ga is compared with Auger electron emitter 111In as a potential therapeutic radionuclide.

Methods: Plasmid pBR322 studies allowed direct comparison between 67Ga and 111In (1 MBq) in causing DNA damage, including the effect of chelators (EDTA and DTPA) and the effects of a free radical scavenger (DMSO). The cytotoxicity of internalized (by means of delivery in the form of oxine complexes) and non-internalized 67Ga and 111In was measured in DU145 prostate cancer cells after a one-hour incubation using cell viability (trypan blue) and clonogenic studies. MDA-MB-231 and HCC1954 cells were also used.

Results: Plasmid DNA damage was caused by 67Ga and was comparable to that caused by 111In; it was reduced in the presence of EDTA, DTPA and DMSO. The A50 values (internalized activity of oxine complexes per cell required to kill 50% of cells) as determined by trypan blue staining was 1.0 Bq/cell for both 67Ga and 111In; the A50 values determined by clonogenic assay were 0.7 Bq/cell and 0.3 Bq/cell for 111In and 67Ga respectively. At the concentrations required to achieve these uptake levels, non-internalized 67Ga and 111In caused no cellular toxicity. Qualitatively similar results were found for MDA-MB-231 and HCC1954 cells.

Conclusion: 67Ga causes as much damage as 111In to plasmid DNA in solution and shows similar toxicity as 111In at equivalent internalized activity per cell. 67Ga therefore deserves further evaluation for radionuclide therapy.

Advances in knowledge and implications for patient care: The data presented here is at the basic level of science. If future in vivo and clinical studies are successful, 67Ga could become a useful radionuclide with little healthy tissue toxicity in the arsenal of weapons for treating cancer.

No MeSH data available.


Related in: MedlinePlus

Clonogenic assay of DU145 cells treated with 111In-oxine or 67Ga-oxine. A: Clonogenicity with increasing cell-bound activities (Bq) per cell. B: Controls for radionuclide oxine treatment: untreated cells, non-cell-bound radioactivity and decayed oxine complexes, standardized to treatment at 15 MBq/mL, achieving uptake of 9.09 ± 1.33 Bq/cell for 111In-oxine and 1.12 ± 0.20 Bq/cell for 67Ga-oxine groups. Data are average ± SD (n = 3/group). Clonogenicity for 111In-oxine at 0.28 ± 0.48% is not visible on the graph.
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f0025: Clonogenic assay of DU145 cells treated with 111In-oxine or 67Ga-oxine. A: Clonogenicity with increasing cell-bound activities (Bq) per cell. B: Controls for radionuclide oxine treatment: untreated cells, non-cell-bound radioactivity and decayed oxine complexes, standardized to treatment at 15 MBq/mL, achieving uptake of 9.09 ± 1.33 Bq/cell for 111In-oxine and 1.12 ± 0.20 Bq/cell for 67Ga-oxine groups. Data are average ± SD (n = 3/group). Clonogenicity for 111In-oxine at 0.28 ± 0.48% is not visible on the graph.

Mentions: A one-hour incubation period with 67Ga-oxine (15 MBq/mL) with cellular uptake as little as 1.1 Bq/cell was enough to diminish clonogenic survival to 4.4% ± 3.1% compared to untreated controls (Fig. 5A). Replacing 67Ga-oxine with 67Ga-citrate at this same concentration, with minimal cellular uptake, caused no significant loss in clonogenicity compared to untreated controls (Fig. 5B). Qualitatively similar results were obtained for 111In demonstrating that neither radionuclide affected clonogenicity significantly unless bound to the cell (Fig. 5B). Fully decayed radioactive 67Ga-oxine and 111In-oxine added to the incubation medium led to a significant decrease in relative clonogenic survival (to 74 ± 17% and 69 ± 20% for decayed 67Ga-oxine and 111In-oxine, respectively, see Fig. 5B) compared to untreated controls. However this chemical toxicity was much less than the toxicity of their non-decayed counterparts, indicating that the radioactivity was by far the major contributor to the observed toxic effect. Qualitatively similar results were found in cell lines MDA-MB-231 and HCC1954 (Figs. S9 and S10 and Table S2).


Re-assessing gallium-67 as a therapeutic radionuclide ☆
Clonogenic assay of DU145 cells treated with 111In-oxine or 67Ga-oxine. A: Clonogenicity with increasing cell-bound activities (Bq) per cell. B: Controls for radionuclide oxine treatment: untreated cells, non-cell-bound radioactivity and decayed oxine complexes, standardized to treatment at 15 MBq/mL, achieving uptake of 9.09 ± 1.33 Bq/cell for 111In-oxine and 1.12 ± 0.20 Bq/cell for 67Ga-oxine groups. Data are average ± SD (n = 3/group). Clonogenicity for 111In-oxine at 0.28 ± 0.48% is not visible on the graph.
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5303015&req=5

f0025: Clonogenic assay of DU145 cells treated with 111In-oxine or 67Ga-oxine. A: Clonogenicity with increasing cell-bound activities (Bq) per cell. B: Controls for radionuclide oxine treatment: untreated cells, non-cell-bound radioactivity and decayed oxine complexes, standardized to treatment at 15 MBq/mL, achieving uptake of 9.09 ± 1.33 Bq/cell for 111In-oxine and 1.12 ± 0.20 Bq/cell for 67Ga-oxine groups. Data are average ± SD (n = 3/group). Clonogenicity for 111In-oxine at 0.28 ± 0.48% is not visible on the graph.
Mentions: A one-hour incubation period with 67Ga-oxine (15 MBq/mL) with cellular uptake as little as 1.1 Bq/cell was enough to diminish clonogenic survival to 4.4% ± 3.1% compared to untreated controls (Fig. 5A). Replacing 67Ga-oxine with 67Ga-citrate at this same concentration, with minimal cellular uptake, caused no significant loss in clonogenicity compared to untreated controls (Fig. 5B). Qualitatively similar results were obtained for 111In demonstrating that neither radionuclide affected clonogenicity significantly unless bound to the cell (Fig. 5B). Fully decayed radioactive 67Ga-oxine and 111In-oxine added to the incubation medium led to a significant decrease in relative clonogenic survival (to 74 ± 17% and 69 ± 20% for decayed 67Ga-oxine and 111In-oxine, respectively, see Fig. 5B) compared to untreated controls. However this chemical toxicity was much less than the toxicity of their non-decayed counterparts, indicating that the radioactivity was by far the major contributor to the observed toxic effect. Qualitatively similar results were found in cell lines MDA-MB-231 and HCC1954 (Figs. S9 and S10 and Table S2).

View Article: PubMed Central - PubMed

ABSTRACT

Introduction: Despite its desirable half-life and low energy Auger electrons that travel further than for other radionuclides, 67Ga has been neglected as a therapeutic radionuclide. Here, 67Ga is compared with Auger electron emitter 111In as a potential therapeutic radionuclide.

Methods: Plasmid pBR322 studies allowed direct comparison between 67Ga and 111In (1 MBq) in causing DNA damage, including the effect of chelators (EDTA and DTPA) and the effects of a free radical scavenger (DMSO). The cytotoxicity of internalized (by means of delivery in the form of oxine complexes) and non-internalized 67Ga and 111In was measured in DU145 prostate cancer cells after a one-hour incubation using cell viability (trypan blue) and clonogenic studies. MDA-MB-231 and HCC1954 cells were also used.

Results: Plasmid DNA damage was caused by 67Ga and was comparable to that caused by 111In; it was reduced in the presence of EDTA, DTPA and DMSO. The A50 values (internalized activity of oxine complexes per cell required to kill 50% of cells) as determined by trypan blue staining was 1.0 Bq/cell for both 67Ga and 111In; the A50 values determined by clonogenic assay were 0.7 Bq/cell and 0.3 Bq/cell for 111In and 67Ga respectively. At the concentrations required to achieve these uptake levels, non-internalized 67Ga and 111In caused no cellular toxicity. Qualitatively similar results were found for MDA-MB-231 and HCC1954 cells.

Conclusion: 67Ga causes as much damage as 111In to plasmid DNA in solution and shows similar toxicity as 111In at equivalent internalized activity per cell. 67Ga therefore deserves further evaluation for radionuclide therapy.

Advances in knowledge and implications for patient care: The data presented here is at the basic level of science. If future in vivo and clinical studies are successful, 67Ga could become a useful radionuclide with little healthy tissue toxicity in the arsenal of weapons for treating cancer.

No MeSH data available.


Related in: MedlinePlus