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Radiobiological effects of the alpha emitter Ra-223 on tumor cells.

ABSTRACT: Targeted alpha therapy is an emerging innovative approach for the treatment of advanced cancers, in which targeting agents deliver radionuclides directly to tumors and metastases. The biological effects of ?-radiation are still not fully understood - partly due to the lack of sufficiently accurate research methods. The range of ?-particles is <100??m, and therefore, standard in vitro assays may underestimate ?-radiation-specific radiation effects. In this report we focus on ?-radiation-induced DNA lesions, DNA repair as well as cellular responses to DNA damage. Herein, we used Ra-223 to deliver ?-particles to various tumor cells in a Transwell system. We evaluated the time and dose-dependent biological effects of ?-radiation on several tumor cell lines by biological endpoints such as clonogenic survival, cell cycle distribution, comet assay, foci analysis for DNA damage, and calculated the absorbed dose by Monte-Carlo simulations. The radiobiological effects of Ra-223 in various tumor cell lines were evaluated using a novel in vitro assay designed to assess ?-radiation-mediated effects. The ?-radiation induced increasing levels of DNA double-strand breaks (DSBs) as detected by the formation of 53BP1 foci in a time- and dose-dependent manner in tumor cells. Short-term exposure (1-8?h) of different tumor cells to ?-radiation was sufficient to double the number of cells in G₂/M phase, reduced cell survival to 11-20% and also increased DNA fragmentation measured by tail intensity (from 1.4 to 3.9) dose-dependently. The ?-particle component of Ra-223 radiation caused most of the Ra-223 radiation-induced biological effects such as DNA DSBs, cell cycle arrest and micronuclei formation, leading ultimately to cell death. The variable effects of ?-radiation onto the different tumor cells demonstrated that tumor cells show diverse sensitivity towards damage caused by ?-radiation. If these differences are caused by genetic alterations and if the sensitivity could be modulated by the use of DNA damage repair inhibitors remains a wide field for further investigations.

SUBMITTER: Bannik K

PROVIDER: S-EPMC6898438 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Radiobiological effects of the alpha emitter Ra-223 on tumor cells.

Bannik Kristina K Madas Balázs B Jarzombek Marco M Sutter Andreas A Siemeister Gerhard G Mumberg Dominik D Zitzmann-Kolbe Sabine S

Scientific reports 20191206 1

Targeted alpha therapy is an emerging innovative approach for the treatment of advanced cancers, in which targeting agents deliver radionuclides directly to tumors and metastases. The biological effects of α-radiation are still not fully understood - partly due to the lack of sufficiently accurate research methods. The range of α-particles is <100 μm, and therefore, standard in vitro assays may underestimate α-radiation-specific radiation effects. In this report we focus on α-radiation-induced D ...[more]

PMID: 31811257

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Project description:Background223Ra is currently used for treatment of metastatic castration resistant prostate cancer patients (mCRPC) bone metastases with fixed standard activity. Individualized treatments, based on adsorbed dose (AD) in target and non-target tissue, are absolutely needed to optimize efficacy while reducing toxicity of α-emitter targeted therapy. This is a pilot first in human clinical trial aimed to correlate dosimetry, clinical response and biological side effects to personalize 223Ra treatment.MethodsOut of 20 mCRPC patients who underwent standard 223Ra treatment and dosimetry, in a subset of 5 patients the AD to target and non-target tissues was correlated with clinical effects and radiation-induced chromosome damages. Before each 223Ra administrations, haematological parameters, PSA and ALP values were evaluated. Additional blood samples were obtained baseline (T0), at 7 days (T7), 30 days (T30) and 180 days (T180) to evaluate chromosome damage. After administration WB planar 223Ra images were obtained at 2-4 and 18-24 h. Treatment response and toxicity were monitored with clinical evaluation, bone scan, 18F-choline-PET/CT, PSA value and ALP while haematological parameters were evaluated weekly after 223Ra injection and 2 months after last cycle.Results1. a correlation between AD to target and clinical response was evidenced with threshold of 20 Gy as a cut-off to obtain tumor control; 2. the AD to red marrow was lower than 2 Gy in all the patients with no apparently correlation between dosimetry and clinical toxicity. 3. a high dose dependent increase of the number of dicentrics and micronuclei during the course of 223Ra therapy was observed and a linear correlation has been found between blood AD (BAD) and number of dicentrics.ConclusionsThis study provides some interesting preliminary evidence to be further investigated: dosimetry may be useful to identify a more appropriate 223Ra administered activity predicting AD to target tissue; a dose dependent complex chromosome damage occurs during 223Ra administration and this injury is more evident in heavily pre-treated patients; dosimetry could be used for radioprotection purpose.Trial registrationThe pilot study has been approved from the Ethics Committee of Regina Elena National Cancer Institute (N:RS1083/18-2111).

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Radiobiological effects of the alpha emitter Ra-223 on tumor cells.

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Radiobiological effects of the alpha emitter Ra-223 on tumor cells.

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