-
Molecules (Basel, Switzerland) Apr 2021Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after... (Review)
Review
Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies (e.g., bisphosphonate and denosumab), hormone therapy, chemotherapy, external beam radiation therapy, and surgical intervention, attempts have been made to use systemic radiotherapy as a means of delivering cytocidal radiation to every bone metastatic lesion. Initially, several bone-seeking beta-minus-particle-emitting radiopharmaceuticals were incorporated into the treatment for bone metastases, but they failed to extend the overall survival in patients. However, recent clinical trials indicate that radium-223 dichloride (RaCl), an alpha-particle-emitting radiopharmaceutical, improves the overall survival of prostate cancer patients with bone metastases. This success has renewed interest in targeted alpha-particle therapy development for visceral and bone metastasis. This review will discuss (i) the biology of bone metastasis, especially focusing on the vicious cycle of bone metastasis, (ii) how bone remodeling has been exploited to administer systemic radiotherapies, and (iii) targeted radiotherapy development and progress in the development of targeted alpha-particle therapy for the treatment of prostate cancer bone metastasis.
Topics: Alpha Particles; Bone Neoplasms; Humans; Ligands; Male; Prostate-Specific Antigen; Prostatic Neoplasms; Radiopharmaceuticals
PubMed: 33918705
DOI: 10.3390/molecules26082162 -
The Quarterly Journal of Nuclear... Dec 2004An important consideration in the development of effective strategies for radioimmunotherapy is the nature of the radiation emitted by the radionuclide. Radionuclides... (Review)
Review
An important consideration in the development of effective strategies for radioimmunotherapy is the nature of the radiation emitted by the radionuclide. Radionuclides decaying by the emission of alpha-particles offer the possibility of matching the cell specific reactivity of monoclonal antibodies with radiation with a range of only a few cell diameters. Furthermore, alpha-particles have important biological advantages compared with external beam radiation and beta-particles including a higher biological effectiveness, which is nearly independent of oxygen concentration, dose rate and cell cycle position. In this review, the clinical settings most likely to benefit from alpha-particle radioimmunotherapy will be discussed. The current status of preclinical and clinical research with antibodies labeled with 3 promising alpha-particle emitting radionuclides - (213)Bi, (225)Ac, and (211)At - also will be summarized.
Topics: Actinium; Alpha Particles; Antibodies, Monoclonal; Astatine; Bismuth; Humans; Isotopes; Neoplasms; Practice Patterns, Physicians'; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals; Treatment Outcome
PubMed: 15640792
DOI: No ID Found -
Molecules (Basel, Switzerland) Nov 2019Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal... (Review)
Review
Targeted alpha-particle therapy (TAT) aims to selectively deliver radionuclides emitting α-particles (cytotoxic payload) to tumors by chelation to monoclonal antibodies, peptides or small molecules that recognize tumor-associated antigens or cell-surface receptors. Because of the high linear energy transfer (LET) and short range of alpha (α) particles in tissue, cancer cells can be significantly damaged while causing minimal toxicity to surrounding healthy cells. Recent clinical studies have demonstrated the remarkable efficacy of TAT in the treatment of metastatic, castration-resistant prostate cancer. In this comprehensive review, we discuss the current consensus regarding the properties of the α-particle-emitting radionuclides that are potentially relevant for use in the clinic; the TAT-mediated mechanisms responsible for cell death; the different classes of targeting moieties and radiometal chelators available for TAT development; current approaches to calculating radiation dosimetry for TATs; and lead optimization via medicinal chemistry to improve the TAT radiopharmaceutical properties. We have also summarized the use of TATs in pre-clinical and clinical studies to date.
Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Humans; Neoplasms; Radioisotopes; Radiometry; Radiopharmaceuticals
PubMed: 31779154
DOI: 10.3390/molecules24234314 -
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 -
Life (Basel, Switzerland) Mar 2023Space missions with humans expose the crews to ionizing radiation, mainly due to the galactic cosmic radiation (GCR). All radiation protection programs in space aim to...
Space missions with humans expose the crews to ionizing radiation, mainly due to the galactic cosmic radiation (GCR). All radiation protection programs in space aim to minimize crews' exposure to radiation. The radiation protection of astronauts can be achieved through the use of shields. The shields could serve as a suit to reduce GCR exposure and, in an emergency, as a radiation shelter to perform necessary interventions outside the space habitat in case of a solar proton event (SPE). A space radiation shielding that is suitable for exploration during space missions requires particular features and a proper knowledge of the radiation type. This study shows the results of numerical simulations performed with the Geant4 toolkit-based code DOSE. Calculations to evaluate the performance of Nomex, an aramidic fiber with high mechanical resistance, in terms of dose reduction to crews, were performed considering the interaction between protons with an energy spectrum ranging from 50 to 1100 MeV and a target slab of 20 g/cm. This paper shows the properties of secondary products obtained as a result of the interaction between space radiation and a Nomex target and the properties of the secondary particles that come out the shield. The results of this study show that Nomex can be considered a good shield candidate material in terms of dose reductions. We also note that the secondary particles that provide the greatest contribution to the dose are protons, neutrons and, in a very small percentage, α-particles and Li ions.
PubMed: 36983945
DOI: 10.3390/life13030790 -
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 -
Clinical Nuclear Medicine Dec 2013Medical oncology is moving toward personalized and precision treatments. This evolution is spearheaded by ongoing discoveries on the fundamental machinery that controls... (Review)
Review
Medical oncology is moving toward personalized and precision treatments. This evolution is spearheaded by ongoing discoveries on the fundamental machinery that controls tumor and hosts microenvironment biological behavior. α-Particles with their high energy and short range had long been recognized as potentially useful in the treatment of cancer. More than a century after the discovery of radium by the Curies, 223Ra dichloride is now available in the expanding armamentarium of therapies for metastatic castration-resistant prostate cancer. This advance occurs in the context of several other novel therapeutics in advanced prostate cancer that include more effective androgen receptor pathway inhibition, better chemotherapy, and immunotherapy. We present a concise review on the therapeutic use of 223Ra dichloride in this clinically important setting including excerpts on the radium history, physical properties, the alpharadin in symptomatic prostate cancer clinical trial, and practical information on its use in the clinic. It is anticipated that, with the current emergence of 223Ra as a viable form of therapy, interest in and use of α-particle therapy in the management of cancer will grow.
Topics: Alpha Particles; Bone Neoplasms; Clinical Trials as Topic; Humans; Male; Prostatic Neoplasms; Radiometry; Radon
PubMed: 24212441
DOI: 10.1097/RLU.0000000000000290 -
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 -
Clinical Cancer Research : An Official... May 2022The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a...
PURPOSE
The anti-CD33 antibody lintuzumab has modest activity against acute myeloid leukemia (AML). To increase its potency, lintuzumab was conjugated to actinium-225 (225Ac), a radionuclide yielding 4 α-particles. This first-in-human, phase I trial was conducted to determine the safety, pharmacology, and biological activity of 225Ac-lintuzumab.
PATIENTS AND METHODS
Eighteen patients (median age, 64 years; range, 45-80) with relapsed or refractory AML received a single infusion of 225Ac-lintuzumab at activities of 18.5 to 148 kBq/kg.
RESULTS
The maximum tolerated dose was 111 kBq/kg. Dose-limiting toxicities included myelosuppression lasting > 35 days in one patient receiving 148 kBq/kg and death from sepsis in two patients treated with 111 and 148 kBq/kg. Myelosuppression was the most common toxicity. Significant extramedullary toxicities were limited to transient grade 3 liver function abnormalities. Pharmacokinetics were determined by gamma counting serial whole blood, plasma, and urine samples at energy windows for the 225Ac daughters, francium-221 and bismuth-213. Two-phase elimination kinetics were seen with mean plasma t1/2 - α and t1/2 - β of 1.9 and 38 hours, respectively. Peripheral blood blasts were eliminated in 10 of 16 evaluable patients (63%) but only at doses of ≥ 37 kBq/kg. Bone marrow blasts were reduced in 10 of 15 evaluable patients (67%), including 3 patients with marrow blasts ≤ 5% and one patient with a morphologic leukemia-free state.
CONCLUSIONS
Therapy for AML with the targeted α-particle generator 225Ac-lintuzumab was feasible with an acceptable safety profile. Elimination of circulating blasts or reductions in marrow blasts were observed across all dose levels.
Topics: Actinium; Alpha Particles; Antibodies, Monoclonal, Humanized; Humans; Immunoconjugates; Leukemia, Myeloid, Acute; Middle Aged
PubMed: 35247915
DOI: 10.1158/1078-0432.CCR-21-3712 -
Journal of Radiation Research Jul 2018Gene expression analysis was carried out in Jurkat cells in order to identify candidate genes showing significant gene expression alterations allowing robust... (Comparative Study)
Comparative Study
Gene expression analysis was carried out in Jurkat cells in order to identify candidate genes showing significant gene expression alterations allowing robust discrimination of the Auger emitter 123I, incorporated into the DNA as 123I-iododeoxyuridine (123IUdR), from α- and γ-radiation. The γ-H2AX foci assay was used to determine equi-effect doses or activity, and gene expression analysis was carried out at similar levels of foci induction. Comparative gene expression analysis was performed employing whole human genome DNA microarrays. Candidate genes had to show significant expression changes and no altered gene regulation or opposite regulation after exposure to the radiation quality to be compared. The gene expression of all candidate genes was validated by quantitative real-time PCR. The functional categorization of significantly deregulated genes revealed that chromatin organization and apoptosis were generally affected. After exposure to 123IUdR, α-particles and γ-rays, at equi-effect doses/activity, 155, 316 and 982 genes were exclusively regulated, respectively. Applying the stringent requirements for candidate genes, four (PPP1R14C, TNFAIP8L1, DNAJC1 and PRTFDC1), one (KLF10) and one (TNFAIP8L1) gene(s) were identified, respectively allowing reliable discrimination between γ- and 123IUdR exposure, γ- and α-radiation, and α- and 123IUdR exposure, respectively. The Auger emitter 123I induced specific gene expression patterns in Jurkat cells when compared with γ- and α-irradiation, suggesting a unique cellular response after 123IUdR exposure. Gene expression analysis might be an effective tool for identifying biomarkers for discriminating different radiation qualities and, furthermore, might help to explain the varying biological effectiveness at the mechanistic level.
Topics: Alpha Particles; Biomarkers; DNA; DNA Damage; Down-Regulation; Gamma Rays; Gene Expression Profiling; Genetic Association Studies; Histones; Humans; Idoxuridine; Jurkat Cells; Signal Transduction; Up-Regulation
PubMed: 29800458
DOI: 10.1093/jrr/rry038