Abstract
BackgroundAuger electron-emitting radionuclides have potential in targeted treatment of small tumors. Thallium-201 (201Tl), a gamma-emitting radionuclide used in myocardial perfusion scintigraphy, decays by electron capture, releasing around 37 Auger and Coster–Kronig electrons per decay. However, its therapeutic and toxic effects in cancer cells remain largely unexplored. Here, we assess 201Tl in vitro kinetics, radiotoxicity and potential for targeted molecular radionuclide therapy, and aim to test the hypothesis that 201Tl is radiotoxic only when internalized.MethodsBreast cancer MDA-MB-231 and prostate cancer DU145 cells were incubated with 200–8000 kBq/mL [201Tl]TlCl. Potassium concentration varied between 0 and 25 mM to modulate cellular uptake of 201Tl. Cell uptake and efflux rates of 201Tl were measured by gamma counting. Clonogenic assays were used to assess cell survival after 90 min incubation with 201Tl. Nuclear DNA damage was measured with γH2AX fluorescence imaging. Controls included untreated cells and cells treated with decayed [201Tl]TlCl.Results201Tl uptake in both cell lines reached equilibrium within 90 min and washed out exponentially (t1/2 15 min) after the radioactive medium was exchanged for fresh medium. Cellular uptake of 201Tl in DU145 cells ranged between 1.6 (25 mM potassium) and 25.9% (0 mM potassium). Colony formation by both cell lines decreased significantly as 201Tl activity in cells increased, whereas 201Tl excluded from cells by use of high potassium buffer caused no significant toxicity. Non-radioactive TlCl at comparable concentrations caused no toxicity. An estimated average 201Tl intracellular activity of 0.29 Bq/cell (DU145 cells) and 0.18 Bq/cell (MDA-MB-231 cells) during 90 min exposure time caused 90% reduction in clonogenicity. 201Tl at these levels caused on average 3.5–4.6 times more DNA damage per nucleus than control treatments.Conclusions201Tl reduces clonogenic survival and increases nuclear DNA damage only when internalized. These findings justify further development and evaluation of 201Tl therapeutic radiopharmaceuticals.
Highlights
Auger electron-emitting radionuclides have potential in targeted treatment of small tumors
By mimicking the biological behavior of potassium, it has played a major role in myocardial perfusion scintigraphy [1], until it was largely replaced by 99mTc labeled complexes [2]. 201Tl has been used for tumor imaging [3, 4], to evaluate chemotherapy responses [5] and tumor malignancy [6, 7]
201Tl kinetics: uptake and efflux In preliminary experiments in RPMI or Dulbecco’s Modified Eagle Medium (DMEM) medium (Table 2), cellular uptake of 201Tl in both DU145 and these results: 90 min incubation time was chosen for radiobiological experiments
Summary
Auger electron-emitting radionuclides have potential in targeted treatment of small tumors. Thallium-201 (201Tl), a gamma-emitting radionuclide used in myocardial perfusion scintigraphy, decays by electron capture, releasing around 37 Auger and Coster–Kronig electrons per decay. 15.3 keV [10] and even though this is comparable to the energy of 125I, its half-life is around 20 times shorter and more amenable to clinical use Auger electronemitters such as 111In,125I and 67Ga (Table 1) [10], have already shown potential for targeted radionuclide therapy of cancer [11,12,13], especially when delivered close to sensitive cellular targets such as DNA and plasma membrane [10, 14, 15]. The therapeutic potential of 201Tl has barely been studied, despite its potent shower of
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