DNA damage in blood leucocytes of prostate cancer patients during therapy with 177Lu-PSMA.

PURPOSE: The aim of this study was to investigate the time- and dose-dependency of DNA double-strand break (DSB) induction and repair in peripheral blood leucocytes of prostate cancer patients during therapy with 177Lu-PSMA. METHODS: Blood samples from 16 prostate cancer patients receiving their first 177Lu-PSMA therapy were taken before and at seven time-points (between 1 h and 96 h) after radionuclide administration. Absorbed doses to the blood were calculated using integrated time-activity curves of the blood and the whole-body. For DSB quantification, leucocytes were isolated, fixed in ethanol and immunostained with γ-H2AX and 53BP1 antibodies. Colocalizing foci of both DSB markers were manually counted in a fluorescence microscope. RESULTS: The average number of radiation-induced foci (RIF) per cell increased within the first 4 h after administration, followed by a decrease indicating DNA repair. The number of RIF during the first 2.6 h correlated linearly with the absorbed dose to the blood (R2 = 0.58), in good agreement with previously published in-vitro data. At late time-points (48 h and 96 h after administration), the number of RIF correlated linearly with the absorbed dose rate (R2 = 0.56). In most patients, DNA DSBs were repaired effectively. However, in some patients RIF did not disappear completely even 96 h after administration. CONCLUSION: The general pattern of the time- and dose-dependent induction and disappearance of RIF during 177Lu-PSMA therapy is similar to that of other radionuclide therapies.

Correlation of the absorbed dose to the blood and DNA damage in leukocytes after internal ex-vivo irradiation of blood samples with Ra-224.

BACKGROUND: Irradiation with α-particles creates densely packed damage tracks along particle trajectories in exposed cells, including complex DNA damage and closely spaced double-strand breaks (DSBs) in hit nuclei. Here, we investigated the correlation of the absorbed dose to the blood and the number of α-induced DNA damage tracks elicited in human blood leukocytes after ex-vivo in-solution exposure with Ra-224. The aim was to compare the data to previously published data on Ra-223 and to investigate differences in DNA damage induction between the two radium isotopes. RESULTS: Blood samples from three healthy volunteers were exposed ex-vivo to six different concentrations of Ra-224 dichloride. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and ß-particles of the Ra-224 decay chain, ranging from 0 to 127 mGy. γ-H2AX + 53BP1 DNA damage co-staining and analysis was performed on ethanol-fixed leukocytes isolated from the irradiated blood samples. For damage quantification, α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci were enumerated in the exposed leukocytes. This revealed a linear relationship between the frequency of α-induced γ-H2AX damage tracks and the absorbed dose to the blood, while the frequency of small γ-H2AX + 53BP1 DSB foci indicative of ß-irradiation was similar to baseline values. CONCLUSIONS: Our data provide a first estimation of the DNA damage induced by Ra-224 in peripheral blood mononuclear cells. A comparison with our previously published Ra-223 data suggests that there is no difference in the induction of radiation-induced DNA damage between the two radium isotopes due to their similar decay properties.