Palliative treatment of metastatic bone pain with radiopharmaceuticals: a perspective beyond Strontium-89 and Samarium-153

PurposeThe present review article aims to provide an overview of the available radionuclides for palliative treatment of bone metastases beyond 89Sr and 153Sm. In addition, it aims to review and summarize the clinical outcomes associated with the palliative treatment of bone metastases using different radiopharmaceuticals.Materials and methodsA literature search was conducted on Science Direct and PubMed databases (1990 - 2015). The following search terms were combined in order to obtain relevant results: bone, metastases, palliative, care, therapy, treatment, radiotherapy, review, radiopharmaceutical, phosphorus-32, strontium-89, yttrium-90, tin-117m, samarium-153, holmium-166, thulium-170, lutetium-177, rhenium-186, rhenium-188 and radium-223. Studies were included if they provided information regarding the clinical outcomes.Results and conclusionsA comparative analysis of the measured therapeutic response of different radiopharmaceuticals, based on previously published data, suggests that there is a lack of substantial differences in palliative efficacy among radiopharmaceuticals. However, when the comparative analysis adds factors such as patients life expectancy, radionuclides physical characteristics (e.g. tissue penetration range and half-life) and health economics to guide the rational selection of a radiopharmaceutical for palliative treatment of bone metastases, 177Lu and 188Re-labeled radiopharmaceuticals appear to be the most suitable radiopharmaceuticals for treatment of small and medium/large size bone lesions, respectively

Computational modeling of radiobiological effects in bone metastases for different radionuclides

: Computational simulation is a simple and practical way to study and to compare a variety ofradioisotopes for different medical applications, including the palliative treatment of bone metastases. Thisstudy aimed to evaluate and compare cellular effects modelled for different radioisotopes currently in use orunder research for treatment of bone metastases using computational methods.Methods: Computational models were used to estimate the radiation-induced cellular effects (VirtualCell Radiobiology algorithm) post-irradiation with selected particles emitted by Strontium-89 (89Sr),Samarium-153 (153Sm), Lutetium-177 (177Lu), and Radium-223 (223Ra).Results: Cellular kinetics post-irradiation using 89Sr β- particles, 153Sm β− particles, 177Lu β− particles and 223Raα particles showed that the cell response was dose- and radio- nuclide-dependent. 177Lu beta minus particlesand, in particular, 223Ra alpha particles, yielded the lowest survival fraction of all investigated particles.Conclusions: 223Ra alpha particles induced the highest cell death of all investigated particles on metastaticprostate cells in comparison to irradiation with β− radionuclides, two of the most frequently used radionuclidesin the palliative treatment of bone metastases in clinical routine practice. Moreover, the data obtained suggestthat the used computational methods might provide some perception about cellular effects following irradiationwith different radionuclides

Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bone metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 (P-32), strontium-89 (Sr-89), yttrium-90 (Y-90), tin-117 (Sn-117m), samarium-153 (Sm-153), holmium-166 (Ho-166), thulium-170 (Tm-170), lutetium-177 (Lu-177), rhenium-186 (Re-186), rhenium-188 (Re-188), and radium-223 (Ra-223). Results: Ra-223 alpha particles, Lu-177 beta minus particles, and Tm-170 beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by Sr-89 and Sm-153, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than Lu-177 beta minus particles and Ra-223 alpha particles. Conclusions: Ra-223 and Lu-177 hold the highest potential for palliative treatment of bone metastases of all radioisotopes compared in this study. Data reported here may prompt future in vitro and in vivo experiments comparing different radionuclides for palliative treatment of bone metastases, raise the need for the careful rethinking of the current widespread clinical use of Sr-89 and Sm-153, and perhaps strengthen the use of Ra-223 and Lu-177 in the palliative treatment of bone metastases. (C) 2014 American Association of Physicists in Medicine

Characterization of Intrinsic Radiation Sensitivity in a Diverse Panel of Normal, Cancerous and CRISPR-Modified Cell Lines

Intrinsic radiosensitivity is a major determinant of radiation response. Despite the extensive amount of radiobiological data available, variability among different studies makes it very difficult to produce high-quality radiosensitivity biomarkers or predictive models. Here, we characterize a panel of 27 human cell lines, including those derived from lung cancer, prostate cancer, and normal tissues. In addition, we used CRISPR-Cas9 to generate a panel of lines with known DNA repair defects. These cells were characterised by measuring a range of biological features, including the induction and repair of DNA double-strand breaks (DSBs), cell cycle distribution, ploidy, and clonogenic survival following X-ray irradiation. These results offer a robust dataset without inter-experimental variabilities for model development. In addition, we used these results to explore correlations between potential determinants of radiosensitivity. There was a wide variation in the intrinsic radiosensitivity of cell lines, with cell line Mean Inactivation Doses (MID) ranging from 1.3 to 3.4 Gy for cell lines, and as low as 0.65 Gy in Lig4−/− cells. Similar substantial variability was seen in the other parameters, including baseline DNA damage, plating efficiency, and ploidy. In the CRISPR-modified cell lines, residual DSBs were good predictors of cell survival (R2 = 0.78, p = 0.009), as were induced levels of DSBs (R2 = 0.61, p = 0.01). However, amongst the normal and cancerous cells, none of the measured parameters correlated strongly with MID (R2 2 = 0.31, p = 0.01) and percentage of cell in S phase (R2 = 0.37, p = 0.005). While these data provide a valuable dataset for the modelling of radiobiological responses, the differences in the predictive power of residual DSBs between CRISPR-modified and other subgroups suggest that genetic alterations in other pathways, such as proliferation and metabolism, may have a greater impact on cellular radiation response. These pathways are often neglected in response modelling and should be considered in the future

DNA repair inhibitors potentiate fractionated radiotherapy more than single-dose radiotherapy in breast cancer cells

SIMPLE SUMMARY: DNA damage response (DDR) inhibitors have been shown to sensitize cells to radiation yet have seen limited application in clinical settings. This could be due to a lack of understanding of how these inhibitors interact with ionizing radiation (IR) dose fractionation and cellular repair. Our study investigated the radiosensitizing effect of different DDR inhibitors on human breast cancer cells, utilizing single-dose and fractionated IR. Their effect on damage repair, DNA double-strand break repair kinetics and cell cycle distribution was also evaluated. The main finding was that radiosensitization by DDR inhibition was more prominent when combined with fractionated IR than single-dose IR. Moreover, DDR inhibition impeded the repair of IR-induced DNA double-strand breaks. Altogether, our study established the radiosensitizing potential of DDR inhibitors while highlighting the importance of IR dose fractionation in similar studies. ABSTRACT: Pharmacological inhibitors of DNA damage response (DDR) proteins, such as the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases and poly (ADP-ribose) polymerase (PARP), have been developed to overcome tumor radioresistance. Despite demonstrating radiosensitization preclinically, they have performed suboptimally in clinical trials, possibly due to an incomplete understanding of the influence of DDR inhibition on ionizing radiation (IR) dose fractionation and sublethal damage repair. Hence, this study aimed to evaluate the radiosensitizing ability under fractionation of ATM inhibitor AZD0156, ATR inhibitor AZD6738 and PARP inhibitor AZD2281 (olaparib), utilizing MDA-MB-231 and MCF-7 human breast cancer cells. Clonogenic assays were performed to assess cell survival and sublethal damage repair after treatment with DDR inhibitors and either single-dose or fractionated IR. Immunofluorescence microscopy was utilized to evaluate DNA double-strand break repair kinetics. Cell cycle distributions were investigated using flow cytometry. All inhibitors showed significant radiosensitization, which was significantly greater following fractionated IR than single-dose IR. They also led to more unrepaired DNA double-strand breaks at 24 h post-IR. This study provides preclinical evidence for the role of AZD0156, AZD6738 and olaparib as radiosensitizing agents. Still, it highlights the need to evaluate these drugs in fractionated settings mirroring clinical practice to optimize the trial design

Synergistic activity of DNA damage response inhibitors in combination with radium-223 in prostate cancer

Radium-223 (223Ra) and Lutetium-177-labelled-PSMA-617 (177Lu-PSMA) are currently the only radiopharmaceutical treatments to prolong survival for patients with metastatic-castration-resistant prostate cancer (mCRPC); however, mCRPC remains an aggressive disease. Recent clinical evidence suggests patients with mutations in DNA repair genes associated with homologous recombination have a greater clinical benefit from 223Ra. In this study, we aimed to determine the utility of combining DNA damage response (DDR) inhibitors to increase the therapeutic efficacy of X-rays, or 223Ra. Radiobiological responses were characterised by in vitro assessment of clonogenic survival, repair of double strand breaks, cell cycle distribution, and apoptosis via PARP-1 cleavage. Here, we show that DDR inhibitors increase the therapeutic efficacy of both radiation qualities examined, which is associated with greater levels of residual DNA damage. Co-treatment of ATM or PARP inhibition with 223Ra increased cell cycle arrest in the G2/M phase. In comparison, combined ATR inhibition and radiation qualities caused G2/M checkpoint abrogation. Additionally, greater levels of apoptosis were observed after the combination of DDR inhibitors with 223Ra. This study identified the ATR inhibitor as the most synergistic inhibitor for both radiation qualities, supporting further pre-clinical evaluation of DDR inhibitors in combination with 223Ra for the treatment of prostate cancer.<br/