astatine and Neoplasms

Despite the consensus around the clinical potential of the α-emitting radionuclide astatine-211 (

Topics: Alpha Particles; Astatine; Clinical Trials as Topic; Cyclotrons; Humans; Neoplasms; Radiation Oncology; Radiopharmaceuticals

Topics: Actinium; Alpha Particles; Astatine; Bismuth; Humans; Neoplasms; Radioisotopes; Radiotherapy; Radium; Thorium

The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue.. We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT.. We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies' pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease.

Topics: Alpha Particles; Animals; Astatine; Humans; Neoplasms; Pharmaceutical Vehicles; Radioisotopes; Single-Domain Antibodies

(211)At is a promising radionuclide for α-particle therapy of cancers. Its physical characteristics make this radionuclide particularly interesting to consider when bound to cancer-targeting biomolecules for the treatment of microscopic tumors. (211)At is produced by cyclotron irradiation of (209)Bi with α-particles accelerated at ~28 MeV and can be obtained in high radionuclidic purity after isolation from the target. Its chemistry resembles iodine, but there is also a tendency to behave as a metalloid. However, the chemical behavior of astatine has not yet been clearly established, primarily due to the lack of any stable isotopes of this element, which precludes the use of conventional analytical techniques for its characterization. There are also only a limited number of research centers that have been able to produce this element in sufficient amounts to carry out extensive investigations. Despite these difficulties, chemical reactions typically used with iodine can be performed, and a number of biomolecules of interest have been labeled with (211)At. However, most of these compounds exhibit unacceptable instability in vivo due to the weakness of the astatine-biomolecule bond. Nonetheless, several compounds have shown high potential for the treatment of cancers in vitro and in several animal models, thus providing a promising basis that has allowed initiation of the first two clinical studies.

Topics: Alpha Particles; Astatine; Humans; Neoplasms; Radiopharmaceuticals

A new high-energy and high-intensity cyclotron, ARRONAX, has been set into operation in 2010. ARRONAX can accelerate both negative ions (H- and D-) and positive ions (He++ and HH+). Protons can be accelerated from 30 MeV up to 70 MeV with a maximum beam intensity of 2 × 375 μAe whereas He++ can be accelerated at 68 MeV with a maximum beam current of 70 μAe. The main fields of application of ARRONAX are radionuclide production for nuclear medicine and irradiation of inert or living materials for radiolysis and radiobiology studies. A large part of the beam time will be used to produce radionuclides for targeted radionuclide therapy (copper-67, scandium-47 and astatine-211) as well as for PET imaging (scandium-44, copper-64, strontium-82 for rubidium-82 generators and germanium-68 for gallium-68 generators). Since the beginning of the project a particular interest has been devoted to alpha-radionuclide therapy using complex ligands like antibodies and astatine-211 has been selected as a radionuclide of choice for such type of applications. Associated with appropriate carriers, all these radionuclides will respond to a maximum of unmet clinical needs.

Topics: Alpha Particles; Astatine; Beta Particles; Cyclotrons; Equipment Design; Humans; Neoplasms; Nuclear Medicine; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals

The 7.2-h half life radiohalogen (211)At offers many potential advantages for targeted α-particle therapy; however, its use for this purpose is constrained by its limited availability. Astatine-211 can be produced in reasonable yield from natural bismuth targets via the (209)Bi(α,2n)(211)At nuclear reaction utilizing straightforward methods. There is some debate as to the best incident α-particle energy for maximizing 211At production while minimizing production of (210)At, which is problematic because of its 138.4-day half life α-particle emitting daughter, (210)Po. The intrinsic cost for producing (211)At is reasonably modest and comparable to that of commercially available (123)I. The major impediment to (211)At availability is attributed to the need for a medium energy α-particle beam for its production. On the other hand, there are about 30 cyclotrons in the world that have the beam characteristics required for (211)At production.

Topics: Alpha Particles; Astatine; Half-Life; Humans; Neoplasms; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals

Targeted radiotherapy using agents tagged with α-emitting radionuclides is gaining traction with several clinical trials already undertaken or ongoing, and others in the advanced planning stage. The most commonly used α-emitting radionuclides are 213Bi, 211At, 223Ra and 225Ac. While each one of these has pros and cons, it can be argued that 211At probably is the most versatile based on its half life, decay scheme and chemistry. On the other hand, for targeting bone metastases, 223Ra is the ideal radionuclide because simple cationic radium can be used for this purpose. In this review, we will discuss the recent developments taken place in the application of 211At-labeled radiopharmaceuticals and give an overview of the current status of 223Ra for targeted α-particle radiotherapy.

Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Astatine; Humans; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Radium

An attractive feature of targeted radionuclide therapy is the ability to select radionuclides and targeting vehicles with characteristics that are best suited for a particular clinical application. One combination that has been receiving increasing attention is the use of monoclonal antibodies (mAbs) specifically reactive to receptors and antigens that are expressed in tumor cells to selectively deliver the alpha-particle-emitting radiohalogen astatine-211 (211At) to malignant cell populations. Promising results have been obtained in preclinical models with multiple 211At-labeled mAbs; however, translation of the concept to the clinic has been slow. Impediments to this process include limited radionuclide availability, the need for suitable radiochemistry methods operant at high activity levels and lack of data concerning the toxicity of alpha-particle emitters in humans. Nonetheless, two clinical trials have been initiated to date with 211At-labeled mAbs, and others are planned for the near future.

Topics: Antibodies, Monoclonal; Astatine; Drug Delivery Systems; Humans; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Staining and Labeling

Advances in diagnostics and targeted radionuclide therapy of haematological and neuroendocrine tumours have raised hope for improved radionuclide therapy of other forms of disseminated tumours. New molecular target structures are characterized and this stimulates the efforts to develop new radiolabelled targeting agents. There is also improved understanding of factors of importance for choice of appropriate radionuclides. The choice is determined by physical, chemical, biological, and economic factors, such as a character of emitted radiation, physical half-life, labelling chemistry, chemical stability of the label, intracellular retention time, and fate of radiocatabolites and availability of the radionuclide. There is actually limited availability of suitable radionuclides and this is a limiting factor for further progress in the field and this is the focus in this article. The probably most promising therapeutic radionuclide, 211At, requires regional production and distribution centres with dedicated cyclotrons. Such centres are, with a few exceptions in the world, lacking today. They can be designed to also produce beta- and Augeremitters of therapeutic interest. Furthermore, emerging satellite PET scanners will in the near future demand long-lived positron emitters for diagnostics with macromolecular radiopharmaceuticals, and these can also be produced at such centres. To secure continued development and to meet the foreseen requirements for radionuclide availability from the medical community it is necessary to establish specialized cyclotron centres for radionuclide production.

Topics: Astatine; Cyclotrons; Drug Delivery Systems; Humans; Neoplasms; Radioisotopes; Tomography, Emission-Computed

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

This synopsis attempts to shed light on the progresses made in the field of cancer therapy using alpha-particles.. The rationale of selection of radionuclides focusing on comparison of alpha- and beta-emitters, the hurdles and their solutions, and recent developments are addressed. The efforts made in the field of alpha-radioimmunotherapy of hematologic malignancies are emphasized. A good deal of progress has been achieved in the past decade, and preclinical studies with a variety of radioimmunoconjugates with astatine and bismuth radioisotopes (At-211, Bi-212, and Bi-213) have generated encouraging results, providing an impetus for future clinical trials.. The onset of early clinical trials with alpha-emitters will hopefully enable the cancer researchers to come up with extremely effective and highly specific "smart bombs" to target cancer cells.

Topics: Actinium; Alpha Particles; Antibodies, Monoclonal; Astatine; Beta Particles; Bismuth; Cell Death; Energy Transfer; Fermium; Humans; Immunoconjugates; Neoplasms; Radioisotopes; Radium; Relative Biological Effectiveness; Terbium

Targeted radiotherapy or endoradiotherapy is an appealing approach to cancer treatment because of the potential for delivering curative doses of radiation to tumor while sparing normal tissues. Radionuclides that decay by the emission of alpha-particles such as the heavy halogen astatine-211 (211At) offer the exciting prospect of combining cell-specific molecular targets with radiation having a range in tissue of only a few cell diameters. Herein, the radiobiological advantages of alpha-particle targeted radiotherapy will be reviewed, and the rationale for using 211At for this purpose will be described. The chemistry of astatine is similar to that of iodine; however, there are important differences which make the synthesis and evaluation of 211At-labeled compounds more challenging. Perhaps the most successful approach that has been developed involves the astatodemetallation of tin, silicon or mercury precursors. Astatine-211 labeled agents that have been investigated for targeted radiotherapy include [211At]astatide, 211At- labeled particulates, 211At-labeled naphthoquinone derivatives, 211At-labeled methylene blue, 211At-labeled DNA precursors, meta-[211At]astatobenzylguanidine, 211At-labeled biotin conjugates, 211At-labeled bisphosphonates, and 211At-labeled antibodies and antibody fragments. The status of these 211At-labeled compounds will be discussed in terms of their labeling chemistry, cytotoxicity in cell culture, as well as their tissue distribution and therapeutic efficacy in animal models of human cancers. Finally, an update on the status of the first clinical trial with an 211At-labeled targeted therapeutic, 211At-labeled chimeric anti-tenascin antibody 81C6, will be provided.

Topics: Alpha Particles; Antibodies, Monoclonal; Astatine; Brachytherapy; DNA; Humans; Neoplasms; Radioimmunotherapy

There can be little doubt that one of the most important problems in the management of cancer is control of metastatic disease. This objective must be achieved ideally with a systemic therapeutic modality that targets cancer cells and gives minimal collateral damage to critical normal cells. The efficacy of targeted cancer therapy relies on the ability of a toxin to be located in the target cancer cell. The ideal toxin is one that is active only in the cancer cell, and not in critical normal cells. Failing this, the next best approach is a toxin with a short effective lifetime to target early stage micrometastatic disease. This rules out chemical toxins, given that they remain effective until excreted from the body, and localization of dose to the cancer cell rules out beta-emitting radio-isotopes (RI). Alpha-emitting RI, however, are much more appropriate toxins because they are short-lived and because their cytotoxicity is the result of their high rate of energy loss and short range of the alpha particles. These radionuclides have properties that are particularly suited for the elimination of single cells in transit or small nests of cancer cells. In vitro and in vivo experiments with alpha RI show dramatic superiority over beta RI. Only a few nuclear hits are needed to kill cells, and the formation of metastatic lung lesions and subcutaneous lesions in mice can be inhibited by systemic administration of alpha emitters. But alpha RI have not been able to control solid tumours, for which beta RI are better suited. A small number of alpha-emitting radionuclides are currently under investigation. These are terbium (Tb)-149, astatine (At)-211, bismuth (Bi)-212 and Bi-213. Terbium-149 and At-211 both require accelerators in close proximity to the place of application. The Bi isotopes are produced by long-lived parents and, as such, can be obtained from generators. The first phase-1 dose escalation trial with Bi-213 radioimmunoconjugate (RIC) commenced in New York in 1997, and other trials are planned with At-211 RIC and At-211 methylene blue for melanoma. Actinium (Ac)-225 is obtained from the decay of thorium (Th)-229, which is a waste product in the enrichment of fissile Th-233. Alternative accelerator production routes are being investigated, beginning with the European Centre for Nuclear Research (CERN) GeV proton spallation source. The ready and low-cost availability of the Ac:Bi generator is an important element in the implementation of clinical trials

Topics: Alpha Particles; Animals; Astatine; Bismuth; Humans; Immunoconjugates; Mice; Neoplasm Metastasis; Neoplasms; Radioisotopes; Terbium; Tumor Cells, Cultured

Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Astatine; Humans; Hyperthermia, Induced; Immunoconjugates; Immunoglobulin Fab Fragments; Neoplasms; Radioimmunotherapy; Yttrium Radioisotopes

Radionuclides such as 211At and 212Bi which decay by the emission of alpha-particles are attractive for certain applications of targeted radiotherapy. The tissue penetration of 212Bi and 211At alpha-particles is equivalent to only a few cell diameters, offering the possibility of combining cell-specific targeting with radiation of similar range. Unlike the beta-particles emitted by radionuclides such as 131I and 90Y, alpha-particles are radiation of high linear energy transfer and thus greater biological effectiveness. Several approaches have been explored for targeted radiotherapy with 212Bi- and 211At-labelled substances including colloids, monoclonal antibodies, metabolic precursors, receptor-avid ligands and other lower molecular weight molecules. An additional agent which exemplifies the promise of alpha-emitting radiopharmaceuticals is meta-[211At]astatobenzylguanidine. The toxicity of this compound under single-cell conditions, determined both by [3H]thymidine incorporation and by limiting dilution clonogenic assays, for human neuroblastoma cells is of the order of 1000 times higher than that of meta-[131I] iodobenzylguanidine. For meta-[211At] astatobenzylguanidine, the Do value was equivalent to only 6-7 211At atoms bound per cell. These results suggest that meta-[211At] astatobenzylguanidine might be valuable for the targeted radiotherapy of micrometastatic neuroblastomas.

Topics: Alpha Particles; Antibodies, Monoclonal; Astatine; Bismuth; Cyclotrons; Humans; Neoplasms; Radioimmunotherapy; Radioisotopes; Radiotherapy

Though great advantages will be connected with endoradiotherapy, a lot of problems has still to be overcome, the greatest of them being without doubt the problem of selectivity of the carrier compounds. Some few of them have proved to be able to accumulate in certain cancers by reason of their incorporation as metabolites, especially in melanomas. The other great hope are the monoclonal antibodies or their fragments, and in this field much endeavour has been spent in the last years. Especially the two-step method of loading the radioactive nuclide to the antibodies when their binding to the cancer cells is complete appears very promising. Some other, unspecific vehicles may also prove suitable for accumulation in certain tumor types. For the selection of the nuclides it has to be considered that radiation biophysical experiments demonstrated that the critical targets for radiation action are with high probability the DNA superstructure units, and that the distribution of ionizations within them is decisive for the inactivation of a cell. With sparsely ionizing radiation (e.g. beta-radiation) rather high doses are required for reaching an adequate concentration of ionizations in these DNA units. Densely ionizing radiation with an LET of about 150 keV/microns exhibits the maximum relative biological effectiveness (12-16 referred to X-radiation). Therefore emitters of alpha-particles the LET of which lies actually somewhat lower, near 100 keV/microns, seem to be very suitable for endoradiotherapy. Moreover the short ranges of these particles (about 60 microns in tissue) render an extensive sparing of the surrounding normal tissue possible. The second group of effective nuclides is that of Auger electron emitters. The low-energy proportion of Auger electrons leads to a high ionization density in small volumes. The very short ranges of these electrons (in the nanometer range), however, require an incorporation of the nuclide into the cell nucleus if an effective cell inactivation is to occur. 211At (alpha-emitter) and 125I (Auger electron emitter) already proved their high inactivating effectiveness in cell cultures and their curative action in animal experiments, and studies of binding 211At to monoclonal antibodies are encouraging. Some other approaches proposed for the transport of radionuclides into tumor cells or for generating them within tumor tissue are also aimed in essential at the release of densely ionizing alpha-particles or of Auger electrons.

Topics: Animals; Astatine; Cell Survival; DNA, Neoplasm; Humans; In Vitro Techniques; Iodine Radioisotopes; Neoplasms; Radioisotopes

The cyclotron-produced radiohalogen, 211At, is eminently suitable as a possible therapeutic radionuclide. It decays by the emission of 6.8 MeV mean energy alpha-particles, which from a radiobiological viewpoint are of near optimal therapeutic LET. This paper reviews developments in the possible application of [211At]astato-labelled molecules as potential anti-tumour agents. Additionally, radio-dosimetric evidence is presented, and its implications for human cancer therapy are discussed.

Topics: Animals; Antibodies, Monoclonal; Astatine; Humans; Melanoma; Naphthoquinones; Neoplasms; Nucleic Acid Precursors; Radiotherapy Dosage

Topics: Alpha Particles; Animals; Astatine; Cricetinae; Electrons; Humans; Idoxuridine; Iodine Radioisotopes; Neoplasms; Radioactivity; Tamoxifen

Probes for radiotheranostics could be produced by introducing radionuclides with similar chemical characteristics into the same precursors. We recently developed an

Topics: Animals; Astatine; Cell Line, Tumor; Drug Stability; Gallium Radioisotopes; Humans; Mice; Neoplasms; Oligopeptides; Positron-Emission Tomography; Radiopharmaceuticals; Tissue Distribution; Xenograft Model Antitumor Assays

Intraperitoneally administered radiolabeled monoclonal antibodies (mAbs) have been tested in several clinical trials, often with promising results, but have never proven curative.

Topics: Alpha Particles; Antibodies, Monoclonal; Astatine; Humans; Models, Biological; Neoplasms; Peritoneum; Radiation Dosage; Radioimmunotherapy; Radiotherapy Dosage; Tumor Burden

Astatine-211 is a promising radionuclide for targeted radiotherapy. It is required to image the distribution of targeted radiotherapeutic agents in a patient's body for optimization of treatment strategies. We proposed to image

Topics: Alpha Particles; Astatine; Computer Simulation; Humans; Monte Carlo Method; Neoplasms; Photons; Radionuclide Imaging; Radiopharmaceuticals; Radiotherapy

To facilitate multicentre clinical studies on targeted alpha therapy, it is necessary to develop an automated, on-site procedure for conjugating rare, short-lived, alpha-emitting radionuclides to biomolecules. Astatine-211 is one of the few alpha-emitting nuclides with appropriate chemical and physical properties for use in targeted therapies for cancer. Due to the very short range of the emitted α-particles, this therapy is particularly suited to treating occult, disseminated cancers. Astatine is not intrinsically tumour-specific; therefore, it requires an appropriate tumour-specific targeting vector, which can guide the radiation to the cancer cells. Consequently, an appropriate method is required for coupling the nuclide to the vector. To increase the availability of astatine-211 radiopharmaceuticals for targeted alpha therapy, their production should be automated. Here, we present a method that combines dry distillation of astatine-211 and a synthesis module for producing radiopharmaceuticals into a process platform. This platform will standardize production of astatinated radiopharmaceuticals, and hence, it will facilitate large clinical studies focused on this promising, but chemically challenging, alpha-emitting radionuclide. In this work, we describe the process platform, and we demonstrate the production of both astaine-211, for preclinical use, and astatine-211 labelled antibodies.

Topics: Antibodies, Monoclonal; Astatine; Automation, Laboratory; Clinical Trials as Topic; Distillation; Humans; Isotope Labeling; Multicenter Studies as Topic; Neoplasms; Radiopharmaceuticals

The cell cluster modeling is a widely used method to estimate the small-scale dosimetry and provides the implication for a clinic. This work evaluated the effect of different regular cluster models on the radiobiological outputs for (211)At-radioimmunotherapy. The cell activity threshold was estimated using a tumor control probability of 0.90. Basically, regular models show similar features with cluster configuration and cell dimension variation. However, their individual results such as the cumulated activity threshold per cell and the prescription dose per volume should not be substituted reciprocally. The tissue composed of smaller cells or midcell packing will need a little more high prescription dose per volume. The radiation sensitivity parameters in a linear-quadratic model are critical to decide the radiobiological response with dose. The cumulated cell activity threshold increases exponentially with α decreasing, and its influence on the big cell dimension is more than on the small one. The different subsources affect radioresistant organs or tissues more remarkably than radiosensitive ones, especially the cells with large cytoplasm. The heterogeneous activity of Gaussian distribution will decrease the therapeutical effectiveness for the nucleus source, but its influence on the cytoplasm and cell surface sources is a little uncertain, as their real mean value is always higher than its set mean value by assuming the cell activity uptakes from zero. Careful usage of underdose with heterogeneous activity distribution should be practiced in clinics. The deteriorated heterogeneous distribution will salvage the potential subversive and lead to the failure of tumor local control. Some cells with no or little activity that are located on the edge or vertex of cube or corner models will have the ability to survive, as there is a lack of a part of the cross-fire dose effect, and so more attention should be paid in selecting the dosage. Although this work focuses on the clinic implication of (211)At in α-radioimmunotherapy, these cell cluster models can be generalized to other radionuclides.

Topics: Astatine; Dose-Response Relationship, Radiation; Linear Models; Models, Biological; Neoplasms; Radiation Tolerance; Radiobiology; Radioimmunotherapy; Radiometry; Radiotherapy Dosage

Technetium-99m (99mTc) has been widely used as an imaging agent but only recently has been considered for therapeutic applications. This study aims to analyze the potential use of 99mTc Auger electrons for targeted tumor radiotherapy by evaluating the DNA damage and its probability of correct repair and by studying the cellular kinetics, following 99mTc Auger electron irradiation in comparison to iodine-131 (131I) beta minus particles and astatine-211 (211At) alpha particle irradiation.. Computational models were used to estimate the yield of DNA damage (fast Monte Carlo damage algorithm), the probability of correct repair (Monte Carlo excision repair algorithm), and cell kinetic effects (virtual cell radiobiology algorithm) after irradiation with the selected particles.. The results obtained with the algorithms used suggested that 99mTc CKMMX (all M-shell Coster-Kroning--CK--and super-CK transitions) electrons and Auger MXY (all M-shell Auger transitions) have a therapeutic potential comparable to high linear energy transfer 211At alpha particles and higher than 131I beta minus particles. All the other 99mTc electrons had a therapeutic potential similar to 131I beta minus particles.. 99mTc CKMMX electrons and Auger MXY presented a higher probability to induce apoptosis than 131I beta minus particles and a probability similar to 211At alpha particles. Based on the results here, 99mTc CKMMX electrons and Auger MXY are useful electrons for targeted tumor radiotherapy.

Topics: Astatine; Computer Simulation; DNA Damage; DNA Repair; Electrons; Fibroblasts; Humans; Intestinal Mucosa; Iodine Radioisotopes; Kinetics; Models, Biological; Monte Carlo Method; Neoplasms; Organotechnetium Compounds; Probability

Topics: Alpha Particles; Astatine; Clinical Trials as Topic; Humans; Neoplasms; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals

211At is an alpha emitter which can be produced with cyclotrons capable of accelerating helium-4 ions to at least 28 MeV in case of external targets. Different targets were used and improved to increase the yield of 211At to amounts considered to be suitable for alpha therapy of tumours.

Topics: Alpha Particles; Astatine; Cyclotrons; Humans; Neoplasms; Phantoms, Imaging

Angiogenesis is a characteristic feature of many aggressive tumours and other disorders. Antibodies capable of binding to new blood vessels, but not to mature vessels, could be used as selective targeting agents for immunoscintigraphic and radioimmunotherapeutic applications. Here we show that scFv(L19), a recombinant human antibody fragment with sub-nanomolar affinity for the ED-B domain of fibronectin, a marker of angiogenesis, can be stably labelled with iodine-125 and astatine-211 with full retention of immunoreactivity, using a trimethyl-stannyl benzoate bifunctional derivative. Biodistribution studies in mice bearing two different types of tumour grafted subcutaneously, followed by ex vivo micro-autoradiographic analysis, revealed that scFv(L19) rapidly localises around tumour blood vessels, but not around normal vessels. Four hours after intravenous injection of the stably radioiodinated scFv(L19), tumour to blood ratios were 6:1 in mice bearing the F9 murine teratocarcinoma and 9:1 in mice bearing an FE8 rat sarcoma. As expected, all other organs (including kidney) contained significantly less radioactivity than the tumour. Since the ED-B domain of fibronectin has an identical sequence in mouse and man, scFv(L19) is a pan-species antibody and the results presented here suggest clinical utility of radiolabelled scFv(L19) for the scintigraphic detection of angiogenesis in vivo. Furthermore, it should now be possible to investigate scFv(L19) for the selective delivery of 211At to the tumour neovasculature, causing the selective death of tumour endothelial cells and tumour collapse.

Topics: Animals; Astatine; Benzoates; Fibronectins; Immunoglobulin Fragments; Iodine Radioisotopes; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Radionuclide Imaging; Radiopharmaceuticals; Regional Blood Flow; Tissue Distribution; Trimethyltin Compounds

Topics: Animals; Astatine; Clinical Trials as Topic; Drug Evaluation; Humans; Neoplasms; Radiopharmaceuticals

Topics: 3-Iodobenzylguanidine; Antineoplastic Agents; Astatine; Carrier Proteins; Genetic Therapy; Guanidines; Humans; Neoplasms; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Radioisotopes; Radiopharmaceuticals; Symporters; Transfection

Astatine-211 is an alpha-emitter with a short half-life (7.2 hr). This paper discusses the potential of 211At targeted by antibodies for tumor therapy and the possible advantage of 211At over beta- and gamma-emitting radionuclides such as 131I currently employed in the field of radioimmunotherapy. Since the longest range alpha-particle from 211At is only 67 microns and the rate of energy loss is high (track averaged linear energy transfer LT approximately 120 keV/micron), a disintegration of 211At produces a large and extremely localized deposition of energy. A Monte-Carlo model has been developed for studying the stochastic fluctuation of alpha-particle hits and energy deposition in cell nuclei in an attempt to determine the efficacy of 211At-labeled antibodies for tumor cell inactivation. Calculations have been performed for 2 extreme conditions: (a) the case of 211At retained in the capillary, and (b) for a homogeneous distribution of 211At-labeled antibody in the tumor. The results of these two calculations represent the boundary conditions between which any real solution must lie. Finally, developments to the model to include antibody transport across the capillary membrane and through the tumor tissue are discussed.

Topics: Antibodies, Neoplasm; Astatine; Humans; Immunotherapy; Monte Carlo Method; Neoplasms; Operations Research; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Computer-Assisted

From the results of the alpha-particle track autoradiography, the alkaline phosphatase studies, the biodistribution investigations and the therapeutic experiments with the transplanted Franks and Hemmings (1978) adenocarcinoma of the rectum in mice, an important finding is the striking selectivity of the uptake of the compound 6-211 At-astato-2-methyl-1, 4-naphthoquinol bis (diphosphate salt), after intraperitoneal injection into the tumour cell nuclei and in many cases into the nuclei of tumour stem cells, together with negligible uptake into normal colon and narrow. The compound, 6-211 At-astato-2-methyl-1, 4-naphthoquinol bis (diphosphate salt) has been found to cure about two-thirds of the transplanted adenocarcinoma of the rectum in mice after a single intra-peritoneal injection of 3-4 microCi. This approach can be regarded as a form of metabolically-directed drug targetting on to a tumour product which is an enzyme, an alkaline phosphatase isozyme, present in the cells of some tumours. The compound is being studied further from the point of view of possible human therapeutic applications.

Topics: Alkaline Phosphatase; Animals; Astatine; Bromine; Energy Transfer; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Neoplasms; Phosphorylation; Radioisotopes; Vitamin K

This report was prepared at the request of the International Atomic Energy Agency and presented at an Advisory Group Meeting on "Applications of Recent Radiobiological Research in Radiotherapy" held in Vienna, Austria, from 24-28 September 1979. Based on the recommendations of the Advisory Group, the I.A.E.A. has decided to initiate a coordinated international research programme entitled "Exploration of the Possibility of high LET RAdiation for Nonconventional Radiotherapy in Cancers". This programme will explore possible applications of corpuscular radiations (neutrons, protons, accelerated heavy ions, negative pi-mesons, thermal and epithermal neutrons) in cancer therapy. In addition, the programme will include research on in situ radiotherapy with unsealed radionuclides and thermal neutron capture. For further information on the programme, please contact Dr T. IWASAKI, Section of Radiation Biology, Division of Life Sciences, International Atomic Energy Agency, Wagramerstrasse 5, P. O. Box 100, A-1400 Vienna, Austria.

Topics: Animals; Antibodies, Neoplasm; Astatine; Cricetinae; Gallium Radioisotopes; Humans; Idoxuridine; Iodine Radioisotopes; Liposomes; Mice; Neoplasms; Radioisotopes; Tamoxifen; Tritium; Vitamin K

Several new approaches to radiation therapy with radionuclides have been discussed. Iron 55 is selectively utilized in the red cell developmental cycle and in therapeutic doses, can lower marrow and circulating erythrocyte levels with much smaller degrees of effect on other cell lines. A serious complication, noted in animal studies, is the induction of neoplasma, especially osteosarcoma. Selective irradiation of the cell nucleus is possible with 125IUdR. This results in highly efficient cell killing due to the highly concentrated region of ionization. High concentrations of densely ionizing radiation in the malignant cell may also be accomplished with 211At. The use of labeled liposomes is an additional approach to the delivery of intracellular irradiation. None of these approaches is applicable for the practical treatment of human malignancy at the present time. The importance of these approaches is their value as models for future development of methods that can provide highly selective radiation to target sites.

Topics: Animals; Astatine; Cell Line; Cell Nucleus; Cell Survival; Cricetinae; Deoxyuridine; DNA; Erythrocytes; Forecasting; Humans; Iodine Radioisotopes; Iron Radioisotopes; Isotope Labeling; Liposomes; Mice; Neoplasms; Neoplasms, Experimental; Radioisotopes; Radiotherapy; Rats

Topics: Adrenal Gland Neoplasms; Animals; Astatine; Female; Humans; Male; Mammary Neoplasms, Animal; Mammary Neoplasms, Experimental; Neoplasms; Neoplasms, Experimental; Neoplasms, Multiple Primary; Neoplasms, Radiation-Induced; Pituitary Neoplasms; Rats; Research; Testicular Neoplasms; Transplantation, Homologous; Uterine Neoplasms

Topics: Animals; Astatine; Isotopes; Neoplasms; Neoplasms, Experimental; Rats; Thyroid Gland