Abstract
Irradiation with high linear energy transfer α-emitters, like the clinically used Ra-223 dichloride, severely damages cells and induces complex DNA damage including closely spaced double-strand breaks (DSBs). As the hematopoietic system is an organ-at-risk for the treatment, knowledge about Ra-223-induced DNA damage in blood leukocytes is highly desirable. Therefore, 36 blood samples from six healthy volunteers were exposed ex-vivo (in solution) to different concentrations of Ra-223. Absorbed doses to the blood were calculated assuming local energy deposition of all α- and β-particles of the decay, ranging from 0 to 142 mGy. γ-H2AX + 53BP1 co-staining and analysis was performed in leukocytes isolated from the irradiated blood samples. For DNA damage quantification, leukocyte samples were screened for occurrence of α-induced DNA damage tracks and small γ-H2AX + 53BP1 DSB foci. 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 β-irradiation was similar to baseline values, being in agreement with a negligible β-contribution (3.7%) to the total absorbed dose to the blood. Our calibration curve will contribute to the biodosimetry of Ra-223-treated patients and early after incorporation of α-emitters.
Highlights
Worldwide, prostate cancer is the second most common cancer in men and has been diagnosed in 1.1 million men in 2012, which accounts for 15% of all incident cancer cases[1]
Since the hematopoietic system is a potential organ-at-risk and the absorbed dose to the blood is often used as a surrogate marker for the absorbed dose to the bone marrow in internal dosimetry[13], it is of great interest to quantify the radiation-induced DNA damage in blood leukocytes after internal irradiation with the α-emitter Ra-223 and to determine the absorbed dose/DNA damage relationship using the early double-strand breaks (DSBs) markers γ-H2AX and 53BP1
We noted that the frequency of α-tracks represents a suitable parameter for biological dose estimation, which is in accordance with recent γ-H2AX studies on DNA damage after internal or external irradiation with α-particles using the γ-H2AX assay[24,33,34,42]
Summary
Prostate cancer is the second most common cancer in men and has been diagnosed in 1.1 million men in 2012, which accounts for 15% of all incident cancer cases[1]. Various single or multi-modality therapeutic options are available to treat metastasis-induced bone pain. These include analgesics, hormone therapy, chemotherapy, external beam radiation, bisphosphonates, or α- or β−-emitting radiopharmaceuticals such as Ra-223 dichloride, Sm-153 EDTMP, and Sr-89 chloride. Of these the α-emitter Ra-223 dichloride is the first licensed radiopharmaceutical that significantly prolongs life in castration-resistant prostate cancer patients with widespread bone metastatic disease as has been shown in the ALSYMPCA trial[4,5]. Double-stranded DNA damage is threatening a cell’s survival or may lead through misrepair to increased mutation load and is of prime interest for clinical applications of genotoxic compounds and www.nature.com/scientificreports/
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
