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Seminars in Nuclear Medicine Mar 2020The short range and high linear energy transfer of α-particles offer the potential for efficient tumor killing while sparing normal bystander cells. Hematologic... (Review)
Review
The short range and high linear energy transfer of α-particles offer the potential for efficient tumor killing while sparing normal bystander cells. Hematologic malignancies are ideally suited to targeted α-particle therapy (TAT) due to easy accessibility of malignant cells in blood, bone marrow, lymph nodes, and spleen as well as their radiosensitivity. Most clinical trials using α-particle therapy for hematologic malignancies have focused on acute myeloid leukemia (AML); however, preclinical studies have shown activity against other diseases such as non-Hodgkin's lymphoma and multiple myeloma. To date, the short-lived radionuclide bismuth-213 (Bi) and its parent actinium-225 (Ac) have been used clinically, but trials with astatinie-211 (At) have recently begun, and thorium-227 (Th) has shown promising preclinical results. Lintuzumab is a humanized monoclonal antibody that targets the cell surface antigen CD33, which is expressed on the vast majority of AML cells. Initial studies showed that Bi-labeled lintuzumab had antileukemic activity and could produce remissions after partial cytoreduction with cytarabine. An initial phase I trial demonstrated that a single infusion of Ac-lintuzumab could be given safely at doses upto 111 kBq/kg with antileukemic activity across all dose levels. A second phase I study showed that fractionated-dose Ac-lintuzumab could be safely combined with low-dose cytarabine and produced objective responses in 28% of older patients with untreated AML. In a phase II study, treatment with Ac-lintuzumab monotherapy for a similar patient population resulted in remission in 69% of patients receiving two fractions of 74 kBq/kg and 22% of patients receiving two 55.5-kBq/kg fractions. Additionally, TAT may be useful in intensifying antileukemic therapy prior to hematopoietic cell transplantation, and pretargeting strategies offer the possibility for improved tumor-to-normal organ dose ratios.
Topics: Alpha Particles; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Molecular Targeted Therapy; Safety
PubMed: 32172800
DOI: 10.1053/j.semnuclmed.2019.09.002 -
JAMA Oncology Dec 2018Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment... (Review)
Review
IMPORTANCE
Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types.
OBSERVATIONS
Theoretically, the high-energy emission of short-range alpha particles causes complex double-stranded DNA breaks, eliciting cell death. No known resistance mechanism to alpha particles has been reported or scientifically established. The short-range emission of alpha particle radiation confines its cytotoxic effect to cancerous lesions and the surrounding tumor microenvironment while limiting toxic effects to noncancerous tissues. The high level of radiobiological effectiveness of alpha particles, in comparison with beta emissions, requires fewer particle tracks to induce cell death. Clinically effective alpha particle-emitting isotopes for cancer therapy should have a short half-life, which will limit long-term radiation exposure and allow for the production, preparation, and administration of these isotopes for clinical use and application. Radium 223 dichloride is the first-in-class, commercially available targeted alpha therapy approved for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases. Given the established overall survival benefit conferred by radium 223 for patients with metastatic castration-resistant prostate cancer, several other targeted alpha therapies are being investigated in clinical trials across many tumor types.
CONCLUSIONS AND RELEVANCE
Targeted alpha therapy represents an emerging treatment approach and provides for the possibility to bypass mechanisms of acquired resistance in selected tumors. In addition, developing novel radionuclide conjugation strategies may overcome targeting limitations. So far, the clinical success of radium 223 has demonstrated the proof of concept for targeted alpha therapy, and future studies may lead to additional treatment options for many cancer types.
Topics: Alpha Particles; Bone Neoplasms; Humans; Male; Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radioisotopes; Radiotherapy; Radium; Therapies, Investigational
PubMed: 30326033
DOI: 10.1001/jamaoncol.2018.4044 -
Current Radiopharmaceuticals 2024The low range of alpha particles provides an opportunity to better target cancer cells theoretically leading to the introduction of interesting alpha emitter... (Review)
Review
The low range of alpha particles provides an opportunity to better target cancer cells theoretically leading to the introduction of interesting alpha emitter radiopharmaceuticals including Ac, Pb, etc. The combination of high energy and short range of alpha emitters differentiates targeted radiotherapy from other methods and reduces unwanted cytotoxicity of the cells around the tumoral tissue. Among interesting alpha emitters candidates for targeted therapy, At, one of the radioisotopes with the best optimal decay properties, shows great promise for targeted radiotherapy in some animal prostate cancer xenograft studies and bone micro tumors with significant effects compared to other beta and alpha emitters and also demonstrates interesting properties for clinical applications. However, production and application of this alpha emitter in the development of actinium-based radiopharmaceuticals is hampered by many obstacles. This mini-review demonstrates At production methods, chemical separation, radiolabeling procedures, At-radiopharmaceuticals and their clinical trials, transport, logistics, and costs and future trends in the field for ultimate clinical applications. This review showed that there are limited clinical trials on Ac-based radiopharmaceuticals, which is due to the low accessibility of this radioisotope and other limitations. However, the development programs of major industries indicate the development of Ac-based radiopharmaceuticals in the future.
Topics: Radiopharmaceuticals; Humans; Astatine; Alpha Particles; Animals; Neoplasms
PubMed: 37937552
DOI: 10.2174/0118744710262325231025075638 -
Cells May 2020Compact chromatin is linked to a poor tumour prognosis and resistance to radiotherapy from photons. We investigated DNA damage induction and repair in the context of...
Compact chromatin is linked to a poor tumour prognosis and resistance to radiotherapy from photons. We investigated DNA damage induction and repair in the context of chromatin structure for densely ionising alpha radiation as well as its therapeutic potential. Chromatin opening by histone deacetylase inhibitor trichostatin A (TSA) pretreatment reduced clonogenic survival and increased γH2AX foci in MDA-MB-231 cells, indicative of increased damage induction by free radicals using gamma radiation. In contrast, TSA pretreatment tended to improve survival after alpha radiation while γH2AX foci were similar or lower; therefore, an increased DNA repair is suggested due to increased access of repair proteins. MDA-MB-231 cells exposed to fractionated gamma radiation (2 Gy × 6) expressed high levels of stem cell markers, elevated heterochromatin H3K9me3 marker, and a trend towards reduced clonogenic survival in response to alpha radiation. There was a higher level of H3K9me3 at baseline, and the ratio of DNA damage induced by alpha vs. gamma radiation was higher in the aggressive MDA-MB-231 cells compared to hormone receptor-positive MCF7 cells. We demonstrate that heterochromatin structure and stemness properties are induced by fractionated radiation exposure. Gamma radiation-exposed cells may be targeted using alpha radiation, and we provide a mechanistic basis for the involvement of chromatin in these effects.
Topics: Acetylation; Alpha Particles; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Clone Cells; Female; Gamma Rays; Heterochromatin; Histones; Humans; Hydroxamic Acids; Lysine; Neoplastic Stem Cells; Radiation Exposure; Spheroids, Cellular
PubMed: 32397212
DOI: 10.3390/cells9051165 -
Annals of the ICRP Oct 2018Systemic or locoregionally administered alpha-particle emitters are highly potent therapeutic agents used in oncology that are fundamentally novel in their mechanism...
Systemic or locoregionally administered alpha-particle emitters are highly potent therapeutic agents used in oncology that are fundamentally novel in their mechanism and, most likely, overcome radiation resistance as the alpha particles emitted have a short range and a high linear energy transfer. The use of alpha emitters in a clinic environment requires extra measures with respect to imaging, dosimetry, and radiation protection. This is shown for the example of Ra dichloride therapy. After intravenous injection, Ra leaves the blood and is taken up rapidly in bone and bone metastases; it is mainly excreted via the intestinal tract. Ra can be imaged in patients with a gamma camera. Dosimetry shows that, after a series of six treatments for a 70-kg person with an overall administered activity of 23 MBq, Ra results in an absorbed alpha dose of approximately 17 Gy to the bone endosteum and approximately 1.7 Gy to the red bone marrow. During administration, special care must be taken to ensure that no spill is present on the skin of either the patient or staff. Due to the low dose rate, the treatment is normally performed on an outpatient basis; the patient and carers should receive written instructions about the therapy and radiation protection.
Topics: Alpha Particles; Humans; Radiation Protection; Radiometry; Radiotherapy; Radiotherapy, Image-Guided; Radium
PubMed: 29664326
DOI: 10.1177/0146645318756253 -
Anti-cancer Agents in Medicinal... 2022One of the most rapidly growing options in the management of cancer therapy is Targeted Alpha Therapy (TAT) through which lethal α-emitting radionuclides conjugated to... (Review)
Review
One of the most rapidly growing options in the management of cancer therapy is Targeted Alpha Therapy (TAT) through which lethal α-emitting radionuclides conjugated to tumor-targeting vectors selectively deliver high amount of radiation to cancer cells.Ac, Bi, At, Bi, and 223Ra have been investigated by plenty of clinical trials and preclinical researches for the treatment of smaller tumor burdens, micro-metastatic disease, and post-surgery residual disease. In order to send maximum radiation to tumor cells while minimizing toxicity in normal cells, a high affinity of targeting vectors to cancer tissue is essential. Besides that, the stable and specific complex between chelating agent and α-emitters was found as a crucial parameter. The present review was planned to highlight recent achievements about TAT-based targeting vectors and chelating agents and provide further insight for future researches.
Topics: Actinium; Alpha Particles; Chelating Agents; Humans; Neoplasms; Radioimmunotherapy; Radium
PubMed: 34315393
DOI: 10.2174/1871520621666210727120308 -
Journal of Nuclear Medicine : Official... Nov 2021Encouraging results from targeted α-therapy have received significant attention from academia and industry. However, the limited availability of suitable radionuclides...
Encouraging results from targeted α-therapy have received significant attention from academia and industry. However, the limited availability of suitable radionuclides has hampered widespread translation and application. In the present review, we discuss the most promising candidates for clinical application and the state of the art of their production and supply. In this review, along with 2 forthcoming reviews on chelation and clinical application of α-emitting radionuclides, will provide a comprehensive assessment of the field.
Topics: Alpha Particles; Radioimmunotherapy
PubMed: 34301779
DOI: 10.2967/jnumed.120.261016 -
Journal of Labelled Compounds &... Sep 2019Targeted alpha therapy (TAT) is a promising approach for the treatment of cancer. The use of alpha emitters for cancer therapy has two distinct advantages over... (Review)
Review
Targeted alpha therapy (TAT) is a promising approach for the treatment of cancer. The use of alpha emitters for cancer therapy has two distinct advantages over conventional therapies. The short range of alpha radiation in human tissue (less than 0.1 mm), corresponding to only a few cell diameters, allows selective killing of targeted cancer cells while sparing surrounding healthy tissue. At the same time, the high energy (several MeV) of alpha radiation and its associated high linear energy transfer leads to highly effective cell kill. Consequently, alpha radiation can destroy cells which otherwise exhibit resistance to treatment with beta or gamma irradiation or chemotherapeutic drugs, and can thus offer a therapeutic option for tumors resistant to conventional therapies. Recent results demonstrating the remarkable therapeutic efficacy of alpha emitters to treat various cancers have underlined the clinical potential of TAT. This paper describes the recent clinical experience with Bi and Ac. In view of the enormous benefit of targeted cancer treatment with alpha emitters, their production will have to be considerably increased beyond current supply capabilities. Alternative production methods based on the irradiation of uranium, thorium, or radium targets at reactors or accelerator facilities have the potential to meet future demand.
Topics: Actinium; Alpha Particles; Bismuth; Humans; Radiochemistry; Radioisotopes; Radiotherapy
PubMed: 31369165
DOI: 10.1002/jlcr.3792 -
Radiation and Environmental Biophysics Nov 2022Exosomes are spherical membrane nanovesicles secreted from cells, and they play an important role in tumor immune response, metastasis, angiogenesis, and survival....
Exosomes are spherical membrane nanovesicles secreted from cells, and they play an important role in tumor immune response, metastasis, angiogenesis, and survival. Studies investigating exosomes isolated from cells exposed to photon radiation commonly used in conventional radiotherapy demonstrate the influence of this type of radiation on exosome characteristics and secretion. There is currently no research investigating the effects of densely ionizing particles such as protons and alpha radiation on exosomes. Thus we have evaluated the cellular response of human prostate cancer cells exposed to 0, 2, and 6 Gy of alpha radiation emitted from the Am-241 source. Irradiated PC3 and DU145 cell lines, characterized by differences in radiosensitivity, were studied using apoptosis, LDH, and IL-6 assays. Additionally, the corresponding concentration and size of isolated exosomes were measured using NTA. We found that exposure to ionizing radiation resulted in gross changes in viability and cell damage. There were increased amounts of apoptotic or necrotic cells as a function of radiation dose. We demonstrated that irradiated PC3 cells secrete higher quantities of exosomes compared to DU145 cells. Additionally, we also found no statistical difference in exosome size for control and irradiated cells.
Topics: Male; Humans; Exosomes; Alpha Particles; PC-3 Cells; Radiation Tolerance; Cell Line, Tumor
PubMed: 36098819
DOI: 10.1007/s00411-022-00991-5 -
Molecules (Basel, Switzerland) Mar 2018This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle... (Review)
Review
This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as alpha-particle generators. It discusses the production of radionuclides like At, Ra, Ac/Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.
Topics: Actinium; Alpha Particles; Astatine; Bismuth; Chelating Agents; Dose-Response Relationship, Radiation; Drug Carriers; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Humans; Neoplasms; Radiation Dosage; Radioisotopes; Radiopharmaceuticals; Radium; Small Molecule Libraries
PubMed: 29510568
DOI: 10.3390/molecules23030581