-
Nature Reviews. Cancer Jun 2015The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has... (Review)
Review
The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types.
Topics: Actinium; Alpha Particles; Antibodies, Monoclonal; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Molecular Targeted Therapy; Neoplasms; Radioimmunotherapy
PubMed: 25998714
DOI: 10.1038/nrc3925 -
Medecine Sciences : M/S Apr 2016Alpha-radioimmunotherapy (α-RIT) is a targeted anti-tumor therapy using usually a monoclonal antibody specific for a tumor antigen that is coupled to an α-particle... (Review)
Review
Alpha-radioimmunotherapy (α-RIT) is a targeted anti-tumor therapy using usually a monoclonal antibody specific for a tumor antigen that is coupled to an α-particle emitter. α-emitters represent an ideal tool to eradicate disseminated tumors or metastases. Recent data demonstrate that ionizing radiation in addition to its direct cytotoxic ability can also induce an efficient anti-tumor immunity. This suggests that biologic effects on irradiated tissues could be used to potentiate immunotherapy efficacy and opens the way for development of new therapies combining α-RIT and different types of immunotherapy.
Topics: Alpha Particles; Animals; Humans; Immune System; Neoplasms; Radioimmunotherapy
PubMed: 27137693
DOI: 10.1051/medsci/20163204014 -
Cancer Research Nov 2019Alpha-emitter radiopharmaceutical therapy (α-RPT) is a treatment modality that is impervious to conventional cellular resistance mechanisms because of the unique...
Alpha-emitter radiopharmaceutical therapy (α-RPT) is a treatment modality that is impervious to conventional cellular resistance mechanisms because of the unique properties of the α-particle. Radiobiological studies of α-particle emitters have been few as they require detailed consideration of both biology and physics. Clinical studies of this radiation delivery modality have shown highly promising results in cancers that are resistant to other treatments. The work by Yard and colleagues published in this issue introduces an innovative approach to radiobiological investigations of α-RPT and highlights the specific physics considerations required to properly investigate this multidisciplinary treatment modality..
Topics: Alpha Particles; Humans; Neoplasms; Radiobiology; Radiopharmaceuticals
PubMed: 31676677
DOI: 10.1158/0008-5472.CAN-19-2806 -
Physics in Medicine and Biology Apr 2022. A systematic review of dosimetry in Targeted Alpha Therapy (TAT) has been performed, identifying the common issues.. The systematic review was performed in accordance... (Review)
Review
. A systematic review of dosimetry in Targeted Alpha Therapy (TAT) has been performed, identifying the common issues.. The systematic review was performed in accordance with the PRISMA guidelines, and the literature was searched using the Scopus and PubMed databases.. From the systematic review, three key points should be considered when performing dosimetry in TAT. (1) Biodistribution/Biokinetics: the accuracy of the biodistribution data is a limit to accurate dosimetry in TAT. The biodistribution of alpha-emitting radionuclides throughout the body is difficult to image directly, with surrogate radionuclide imaging, blood/faecal sampling, and animal studies able to provide information. (2) Daughter radionuclides: the decay energy of the alpha-emissions is sufficient to break the bond to the targeting vector, resulting in a release of free daughter radionuclides in the body. Accounting for daughter radionuclide migration is essential. (3) Small-scale dosimetry and microdosimetry: due to the short path length and heterogeneous distribution of alpha-emitters at the target site, small-scale/microdosimetry are important to account for the non-uniform dose distribution in a target region, organ or cell and for assessing the biological effect of alpha-particle radiation.. TAT is a form of cancer treatment capable of delivering a highly localised dose to the tumour environment while sparing the surrounding healthy tissue. Dosimetry is an important part of treatment planning and follow up. Being able to accurately predict the radiation dose to the target region and healthy organs could guide the optimal prescribed activity. Detailed dosimetry models accounting for the three points mentioned above will help give confidence in and guide the clinical application of alpha-emitting radionuclides in targeted cancer therapy.
Topics: Alpha Particles; Animals; Monte Carlo Method; Neoplasms; Radioisotopes; Radiometry; Tissue Distribution
PubMed: 35316802
DOI: 10.1088/1361-6560/ac5fe0 -
Cancer Treatment Reviews Jul 2018With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can... (Review)
Review
With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can potentially reduce side effects caused by radiation in normal tissues and increased destructive radiobiological effects in tumor cells. However, in many countries, the use of this therapy is still in a pioneering phase. Radium-223 (Ra), an alpha-emitting radionuclide, has been the first of its kind to be approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. Nevertheless, the interaction mechanism and the direct effects of this radiopharmaceutical in tumor cells are not fully understood neither characterized at a molecular level. In fact, the ways how TAT is linked to radiobiological effects in cancer is not yet revised. Therefore, this review introduces some physical properties of TAT that leads to biological effects and links this information to the hallmarks of cancer. The authors also collected the studies developed with Ra to correlate with the three categories reviewed - properties of TAT, 5 R's of radiobiology and hallmarks of cancer- and with the promising future to this radiopharmaceutical.
Topics: Alpha Particles; Animals; Bone Neoplasms; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Radium
PubMed: 29859504
DOI: 10.1016/j.ctrv.2018.05.011 -
PloS One 2023DNA double strand breaks (DSBs) are a deleterious form of DNA damage. Densely ionising alpha radiation predominantly induces complex DSBs and sparsely ionising gamma...
DNA double strand breaks (DSBs) are a deleterious form of DNA damage. Densely ionising alpha radiation predominantly induces complex DSBs and sparsely ionising gamma radiation-simple DSBs. We have shown that alphas and gammas, when applied simultaneously, interact in producing a higher DNA damage response (DDR) than predicted by additivity. The mechanisms of the interaction remain obscure. The present study aimed at testing whether the sequence of exposure to alphas and gammas has an impact on the DDR, visualised by live NBS1-GFP (green fluorescent protein) focus dynamics in U2OS cells. Focus formation, decay, intensity and mobility were analysed up to 5 h post exposure. Focus frequencies directly after sequential alpha → gamma and gamma → alpha exposure were similar to gamma alone, but gamma → alpha foci quickly declined below the expected values. Focus intensities and areas following alpha alone and alpha → gamma were larger than after gamma alone and gamma → alpha. Focus movement was most strongly attenuated by alpha → gamma. Overall, sequential alpha → gamma exposure induced the strongest change in characteristics and dynamics of NBS1-GFP foci. Possible explanation is that activation of the DDR is stronger when alpha-induced DNA damage precedes gamma-induced DNA damage.
Topics: Alpha Particles; Gamma Rays; Records; DNA Breaks, Double-Stranded; DNA Damage; Green Fluorescent Proteins
PubMed: 37307266
DOI: 10.1371/journal.pone.0286902 -
Current Radiopharmaceuticals 2018The development of radiopharmaceuticals containing 225Ac for targeted alpha therapy is an active area of academic and commercial research worldwide. (Review)
Review
BACKGROUND
The development of radiopharmaceuticals containing 225Ac for targeted alpha therapy is an active area of academic and commercial research worldwide.
OBJECTIVES
Despite promising results from recent clinical trials, 225Ac-radiopharmaceutical development still faces significant challenges that must be overcome to realize the widespread clinical use of 225Ac. Some of these challenges include the limited availability of the isotope, the challenging chemistry required to isolate 225Ac from any co-produced isotopes, and the need for stable targeting systems with high radiolabeling yields.
RESULTS
Here we provide a review of available literature pertaining to these challenges in the 225Acradiopharmaceutical field and also provide insight into how performed and planned efforts at TRIUMF - Canada's particle accelerator centre - aim to address these issues.
Topics: Actinium; Alpha Particles; Humans; Neoplasms; Radiochemistry; Radionuclide Generators; Radiopharmaceuticals
PubMed: 29658444
DOI: 10.2174/1874471011666180416161908 -
Physics in Medicine and Biology Jan 2020Diffusing alpha-emitters radiation therapy ('DaRT') is a new cancer-treatment modality, which enables treating solid tumors by alpha particles. The treatment utilizes...
Diffusing alpha-emitters radiation therapy ('DaRT') is a new cancer-treatment modality, which enables treating solid tumors by alpha particles. The treatment utilizes implantable seeds embedded with a low activity of radium-224. Each seed continuously emits the short-lived alpha-emitting daughters of radium-224, which spread over several mm around it, creating a 'kill region' of high alpha-particle dose. DaRT is presently tested in clinical trials, starting with locally advanced and recurrent squamous cell carcinoma (SCC) of the skin and head and neck, with promising results with respect to both efficacy and safety. This work aims to provide a simple model which can serve as a zero-order approximation for DaRT dosimetry, allowing for calculating the macroscopic alpha particle dose of a point source, as a basis for more realistic source geometries. The model consists of diffusion equations for radon-220, lead-212 and bismuth-212, with the other short-lived daughters in local secular equilibrium. For simplicity, the medium is assumed to be homogeneous, isotropic and time-independent. Vascular effects are accounted for by effective diffusion and clearance terms. To leading order, the alpha particle dose can be described by simple analytic expressions, which shed light on the underlying physics. The calculations demonstrate that, for a reasonable choice of model parameters, therapeutic alpha-particle dose levels are obtained over a region measuring 4-7 mm in diameter for sources carrying a few [Formula: see text]Ci of radium-224. The model predictions served as the basis for treatment planning in the SCC clinical trial, where treatments employing DaRT seeds carrying 2 [Formula: see text]Ci of radium-224 and spaced 5 mm apart resulted in ∼[Formula: see text] complete response of the treated tumors with no observed radiation-induced toxicity. The promising results of the SCC clinical trial indicate that in spite of its approximate nature, the simple diffusion-based dosimetry model provides a quantitative starting point for DaRT treatment planning.
Topics: Alpha Particles; Bismuth; Brachytherapy; Diffusion; Dose Fractionation, Radiation; Head and Neck Neoplasms; Humans; Kinetics; Lead Radioisotopes; Radioisotopes; Radiometry; Radium; Radon; Squamous Cell Carcinoma of Head and Neck; Thorium
PubMed: 31766047
DOI: 10.1088/1361-6560/ab5b73 -
International Journal of Radiation... 2022Radium is the most common source of alpha radiation exposure to humans and non-human species in the environment but the dosimetry is complicated by the decay chain which...
PURPOSE
Radium is the most common source of alpha radiation exposure to humans and non-human species in the environment but the dosimetry is complicated by the decay chain which involves gamma exposure due to radon daughters. This paper seeks to determine the separate contributions of alpha and gamma doses to the total dose and total direct and non-targeted effect in a fish and a human cell line.
MATERIALS AND METHODS
This study aimed to isolate the effect of alpha particles following exposure to low doses of radium in cells, and their progeny which received no further exposure. This was initially done by comparing the survival values of a human keratinocyte cell line (HaCaT) and an embryonic Chinook salmon cell line (CHSE-214) exposed to gamma radiation, from survival of the same cell lines exposed to mixed alpha and gamma radiation through exposure to Ra-226 and its decay products. A Monte Carlo simulation was later performed to determine the contributions of radium decay products including radon daughters.
RESULTS
The human cell line showed increased radioresistance when exposed to low doses of alpha particles. In contrast the fish cell line, which demonstrated radioresistance to low dose gamma radiation, showed increased lethality when exposed to low doses of alpha particles. Significant and complex levels of non-targeted effects were induced in progeny of irradiated cells. The simulation showed that gamma and beta decay products did not contribute significant dose and the highest beta dose was below the threshold for inducing non-targeted effects.
CONCLUSIONS
The results confirm the need to consider the dose-response relationship when developing radiation weighting factors for low dose exposures, as well as the need to be aware of possible cell line and species differences.
Topics: Alpha Particles; Animals; Radiation Exposure; Radiometry; Radium; Radon; Radon Daughters
PubMed: 33332185
DOI: 10.1080/09553002.2020.1866226 -
International Journal of Radiation... 2021The development of an exposure apparatus for in situ α-irradiation studies of cells. The construction of the apparatus is simple and the apparatus is maintenance free,...
PURPOSE
The development of an exposure apparatus for in situ α-irradiation studies of cells. The construction of the apparatus is simple and the apparatus is maintenance free, easy to use and of low cost. This small device can be placed in an incubator, where the exposure environment is controlled. Moreover the vapor saturated incubator protects the cells from drying out, allowing long irradiation intervals.
MATERIALS AND METHODS
The system includes a U alpha (α)-source of total activity 0.77 ± 0.03 MBq in the form of a thin disk deposited on an aluminum substrate. The α-particles emitted in the air have a mean energy of 4.9 MeV at the disk surface. Source homogeneity has been studied via Rutherford Backscattering Spectrometry. Using SRIM 2013 and Monte Carlo (MC) simulations via the MCNP6.1 code, LET and energy deposition values have been calculated for various filling gasses. Furthermore, based on these simulations, the assembly's dimensions and equivalent irradiation rate have been determined. With respect to the aforementioned dimensions, the experimental setup is constructed in a way to provide uniform irradiation of the sample. Using irradiation radial homogeneity has been studied. In order to evaluate biologically our apparatus, a well-established chromosomal aberration assay has been utilized, applied in exponentially growing hamster (CHO) cells. Furthermore, immunofluorescence gamma-H2AX/53BP1 foci assay has been performed as a 'biological detector', in order to validate α-particles surface density.
RESULTS
Source surface homogeneity: emission deviations do not exceed 10-15%. The optimal distance between the source and the cells for irradiation is determined to be 14.8 mm. Irradiation radial homogeneity: a deviation of 5% occurs at the first 8 mm from the center of the irradiation area, and a 10% deviation occurs after 12 mm. Chromosomal aberrations were found in good agreement with the corresponding in bibliography.
CONCLUSIONS
The current technical report describes analytically the development and evaluation stages of this experimental housing; from MC simulations to the irradiation of mammalian cells and data analysis. Moreover, guidance is provided as well as a report of the variables on which critical parameters are depended, so as to make this work useful to anyone who wants to construct a similar in-house α-irradiation apparatus for radiobiological studies using mammalian cells.
Topics: Alpha Particles; Animals; Chromosome Aberrations; Cricetinae; Monte Carlo Method; Radiobiology
PubMed: 34330206
DOI: 10.1080/09553002.2021.1962568