Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Astatine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources
PubMed2005

A new internal target system for production of (211)At on the cyclotron U-120M.

The alpha emitter (211)At is a radionuclide with good potential for use in the therapy of smaller tumours and metastases. However, limited availability of this radionuclide hinders development of this application and the research of astatine chemistry in general. In this general context we have designed and tested a new internal target system. A thin bismuth layer (3-5 microm) was evaporated onto a light target backing (7.5 g) and irradiated at 0.5-1.5 degrees angles with 29.5 MeV alpha particles beam of intensity up to 30 microA. The backing was then released from the target holder and used directly for astatine separation via dry distillation. Astatine condensed on the Teflon capillary walls was then eluted into 150-250 microl of methanol. The saturation yield was found to be ca. 400 MBq/microA, and the radionuclidic purity of (211)At acceptable for medical applications (activity ratio (210)At/(211)At<10(-3) at EOB). The overall separation yield was 65-75%.

Journal Article↗
PubMed1988

Preliminary observations of malignant melanoma therapy using radiolabeled alpha-methyltyrosine.

A strategy for cancer therapy using astatine-211-labeled alpha-methyltyrosine (211At-AMT) was studied in cultured B16 melanoma cells and compared to the radiotoxicity of iodine-125-labeled iododeoxyuridine (125IUdR), a thymidine analogue. Both 125I and 211At deliver lethal doses of irradiation to melanoma cells when administered as 125IUdR and 211At-AMT. The alpha decay of astatine-211 is more effective however, needing only a fraction of the cellular radioactivity of 125IUdR to effect comparable clonogenic survival. Compared with 125IUdR, 125I-AMT is not cytotoxic because the range of the low energy electrons released does not interact with DNA. Uptake of radiolabeled AMT by melanotic cells is enhanced by theophylline. This preliminary evidence suggests that 211At-labeled melanin precursors may be exquisitely cytotoxic to B16 melanoma cells.

Astatine↗
PubMed1993

Preparation and evaluation of para-[211At]astatobenzoyl labeled anti-renal cell carcinoma antibody A6H F(ab')2. In vivo distribution comparison with para-[125I]iodobenzoyl labeled A6H F(ab')2.

A preliminary investigation of an 211At labeled anti-renal cell carcinoma antibody fragment, A6H F(ab')2, was conducted. In the investigation, A6H F(ab')2 was labeled by conjugation with N-succinimidyl p-[211At]astatobenzoate, and the in vivo biodistribution was evaluated in athymic mice bearing TK-82 renal cell carcinoma xenografts. As a control, p-[125I]iodobenzoyl labeled A6H F(ab')2 was coinjected with the astatinated F(ab')2. The data obtained demonstrated that the two radiolabels (211At and 125I) had quite similar distributions, providing evidence that the 211At remained attached to the A6H F(ab')2 in vivo. Further, the astatinated antibody attained a 2:1 tumor-to-blood ratio, and greater than 35:1 tumor-to-muscle ratio, at 4h post-injection, suggesting that this antibody conjugate could be used to evaluate treatment of metastatic renal cell carcinoma in a mouse model.

Animals↗
PubMed1986

Animal studies on the in vivo stability of 211At-labelled albumin particles.

The alpha-emitter astatine-211 appears as one of the most suitable representatives for radiotherapy owing to its excellent decay properties. We report the studies in mice on the stability of the astatine bond to HSA-particles. Microspheres stick fast in the lung capillaries. There is a comparatively very slow decrease of radioactivity in the lungs. The 211At-labelled microspheres appear quite stable in vivo compared with a series of other biomolecules and so give a potential possibility for using the excellent radiophysical features of 211At in endogenous therapy of malignant tumours.

Animals↗
PubMed2002

Vascular-targeted radioimmunotherapy with the alpha-particle emitter 211At.

Astatine-211, an alpha-particle emitter, was employed in a model system for vascular-targeted radioimmunotherapy of small tumors in mouse lung to compare its performance relative to other radioisotopes in the same system. Astatine-211 was coupled to the lung blood vessel-targeting monoclonal antibody 201B with N-succinimidyl N-(4-[211At]astatophenethyl) succinamate linker. Biodistribution data showed that the conjugate delivered 211At to the lung (260-418% ID/g), where it remained with a biological half-time of about 30 h. BALB/c mice bearing about 100 lung tumor colonies of EMT-6 cells, each about 2000 cells in size, were treated with 211At-labeled monoclonal antibody 201B. The administered activity of 185 kBq per animal extended the life span of treated mice over untreated controls. Injections of 370 kBq, corresponding to an absorbed dose of 25-40 Gy, were necessary to eradicate all of the lung tumors. Mice receiving 740 kBq of 211At-labeled monoclonal antibody 201B developed pulmonary fibrosis 3-4 months after treatment, as did mice treated with 3700 kBq of the alpha-particle emitter 213Bi-labeled monoclonal antibody 201B in previous work. Animals that were injected with 211At bound to untargeted IgG or to glycine, as control agents, also demonstrated therapeutic effects relative to untreated controls. Control groups that received untargeted 211At required about twice as much administered activity for effective therapy as did groups with lung-targeted radioisotope. These results were not consistent with radioisotope biodistribution and dosimetry calculations that indicated that lung-targeted 211At should be at least 10-fold more efficient for lung colony therapy than 211At bound to nontargeting controls. The data showed that 211At is useful for vascular-targeted radioimmunotherapy because lung tumor colonies were eradicated in the mice. Work in this model system demonstrates that vascular targeting of alpha-particle emitters is an efficient therapy for small perivascular tumors and may be applicable to human disease when specific targeting agents are identified.

Alpha Particles↗
PubMedDate not supplied

In vitro effects of free 211At,211At-albumin and 211At-monoclonal antibody compared to external photon irradiation on two human cancer cell lines.

BACKGROUND: The aim of this study was to perform various 211At irradiations of importance for the evaluation of 211At-radioimmunotherapy, and compare the effect with that of low linear energy transfer (LET) radiation. MATERIALS AND METHODS: All irradiations were performed on low-concentration single-cell suspensions. Growth assays using 96-well plates were used to estimate apparent cell survival. Centrifuge tube filters were used to estimate the cell uptake and binding of 211At. RESULTS: A relative biological effect (RBE) of 12 +/- 2 (Colo-205) and 5.3 +/- 0.7 (OVCAR-3) was found from 211At-albumin irradiations. There was a 174 +/- 28 times higher free 211At concentration in the cell fraction than in the surrounding medium. For 211At-MAb, an 8,000-30,000 times higher concentration in the cell fraction was achieved, compared to the medium. Corrected for the uptake, an average of 31 +/- 2 ([211At]-astatine) or 26 +/- 5 ([211At]-MAb) decays per cell were required for 37% survival of Colo-205 cells. An average of 19 +/- 3 decays ([211At]-astatine) were required per OVCAR-3 cell. CONCLUSIONS: Cell uptake and binding of 211At was unexpectedly high, possibly favouring its therapeutic use. The binding is probably to the cell surface. The RBE is 5.3 +/- 0.7 for OVCAR-3 and 12 +/- 2 for Colo-205 cells.

Antibodies, Monoclonal↗
PubMed2003

(211)At-labeled and biotinylated effector molecules for pretargeted radioimmunotherapy using poly-L- and poly-D-Lysine as multicarriers.

Poly-L- and poly-D-lysine were evaluated as carriers of astatine and biotin for prospective use as effector molecules in pretargeted radioimmunotherapy of micrometastases. The precursor polylysine was derivatized in a three-step, single-pot procedure, including biotinylation with biotin amidocaproic N-hydroxysuccinimide, astatination via the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate, and, finally, charge modification using succinic anhydride. The chemistry was shown to be very facile, with a biotinylation efficiency of 75 +/- 5%, and overall radiochemical yields in the range of 50-70%. After charge modification, no amines could be detected in the final product. The biotin function was unaffected by the chemistry and the radiation, as confirmed by almost complete binding of the effector molecule to avidin beads using a convenient filter tube assay. The effector molecules were evaluated in tumor-free female nude mice with regard to whole-body retention and tissue distribution after i.p. administration. The distribution of the L-isomer effector molecule showed rapid whole-body clearance with low uptake in all tissues, whereas the D-isoform showed whole-body clearance related to uptake in the kidneys. Both D-isomer and L-isomer showed faster blood clearance and generally lower tissue uptakes than labeled antibodies. The normal tissue distribution after the peritoneal administration implies that pretargeting using L-structure polylysine as the effector molecule may give a higher therapeutic index than that achieved in conventional radioimmunotherapy.

Animals↗
PubMedDate not supplied

No-carrier-added (4-fluoro-3-[131I]iodobenzyl)guanidine and (3-[211At]astato-4-fluorobenzyl)guanidine.

With 3-bromo-4-fluorotoluene as starting material, [4-fluoro-3-(trimethylsilyl)benzyl]guanidine was prepared in five steps in 1.5% overall yield. Radioiodination of this silicon precursor using N-chlorosuccinimide in trifluoroacetic acid at room temperature for 5 min gave (4-fluoro-3-[131I]-iodobenzyl)guanidine ([131I]FIBG) in 50-60% radiochemical yield. A byproduct which had a retention time in two HPLC systems similar to that of (m-iodobenzyl)guanidine (MIBG) was formed in about 30% yield. [131I]FIBG was stable up to 3 h under these conditions of iodination, indicating that the byproduct is not generated as a result of [131I]FIBG degradation. Using hydrogen peroxide as the oxidant in aqueous medium and a reaction time of 30 min at 50 degrees C, yields of [131I]FIBG could be increased to 75-80%, with less than 7% of the byproduct formed under these conditions. Astatination of the silicon precursor using N-chlorosuccinimide in trifluoroacetic acid at 70 degrees C gave 65-70% radiochemical yield of (3-[211At]astato-4-fluorobenzyl)guanidine ([211At]AFBG) in 10-15 min; about 17% of the byproduct formation was seen. Astatination of the silicon precursor under aqueous conditions using hydrogen peroxide was not successful.

Amino Acids↗
PubMed2006

Two-component relativistic density-functional calculations of the dimers of the halogens from bromine through element 117 using effective core potential and all-electron methods.

A two-component quasirelativistic Hamiltonian based on spin-dependent effective core potentials is used to calculate ionization energies and electron affinities of the heavy halogen atom bromine through the superheavy element 117 (eka-astatine) as well as spectroscopic constants of the homonuclear dimers of these atoms. We describe a two-component Hartree-Fock and density-functional program that treats spin-orbit coupling self-consistently within the orbital optimization procedure. A comparison with results from high-order Douglas-Kroll calculations--for the superheavy systems also with zeroth-order regular approximation and four-component Dirac results--demonstrates the validity of the pseudopotential approximation. The density-functional (but not the Hartree-Fock) results show very satisfactory agreement with theoretical coupled cluster as well as experimental data where available, such that the theoretical results can serve as an estimate for the hitherto unknown properties of astatine, element 117, and their dimers.

Journal Article↗
PubMed2000

Potential use of radiolabeled glucuronide prodrugs with auger and/or alpha emitters in combined chemo- and radio-therapy of cancer.

Nowadays, the scientists from different disciplines have focused their attentions to new anticancer drug design for cancer chemotherapy. An effective anticancer drug should ensure the selective drug incorporation into the targeted tumor cells without principally incorporation into the normal cells. So, the targeted tumor cells can selectively be damaged by the cytotoxic effectiveness of the drug. The basic principles of drug design have involved "prodrug" concept, which means a chemical agent which is not itself active as an anticancer drug, but it can be transformed to an active form after its administration. Prodrugs can finally be activated onto the tumor cells by some kind of enzymes. In this context, the activation of glucuronide prodrugs by b-glucuronidase have a large potential applications in cancer chemotherapy. On the other hand, combined chemo- and radio-therapy of cancer (CCRTC) concept aims to combine the cytotoxicity of an aglycone with the radiotoxicity of an appropriate radionuclide on the same prodrug. So, the cytotoxic and radiotoxic effectiveness' will be able to be concentrated into the same tumor cell to increase obviously its damage. For experimental realization of this concept an effective anticancer prodrug should be radiolabeled with a radionuclide having high level of radiotoxic effectiveness such as Auger and/or alpha-emitter radionuclides. Iodine-125 and astatine-211 are very interesting radionuclides as being effective Auger and/or alpha-emitters. Briefly, the glucuronide prodrugs radiolabeled with iodine-125 or astatine-211 promise to be designed very effective anticancer agents in the future applications of cancer chemotherapy.

Animals↗
PubMed1994

Meta-[211At]astatobenzylguanidine: further evaluation of a potential therapeutic agent.

Meta-[211At]astatobenzylguanidine ([211At]MABG) is an astatinated analogue of meta-iodobenzylguanidine (MIBG) that could be of value for therapeutic applications. The initial goal of this study was to determine whether [211At]MABG is taken up, like MIBG, by a specific uptake-I mechanism. Norepinephrine and desipramine (DMI) decreased [211At]MABG uptake in SK-N-SH human neuroblastoma cells. This uptake was found to be energy-dependent: In mice, pre-treatment with DMI reduced uptake of [211At]MABG at 1 hr post-injection in the adrenal and in the heart. Tetrabenazine at a dose of 40 mg/kg reduced uptake of [211At]MABG in the mouse heart in vivo (69% of control) whereas up to 100 microM of tetrabenazine did not affect the in vitro uptake of [211At]MABG in SK-N-SH cells. In SK-N-SH cells, 53% and 38%, respectively, of the initial uptake of [211At]MABG was retained at 4 hr and 6 hr. For no-carrier-added (n.c.a.) [131I]MIBG these values were similar, 60% and 48%. The ability of SK-N-SH cells to incorporate [3H]thymidine was reduced to less than 50% of control values when treated with as little as 3.2 nCi of [211At]MABG. In contrast, no significant reduction in the thymidine uptake was observed, even with 80 nCi of n.c.a. MIBG.

3-Iodobenzylguanidine↗
PubMed2003

Combined effect of gefitinib ('Iressa', ZD1839) and targeted radiotherapy with 211At-EGF.

The EGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) gefitinib ['Iressa' (trademark of the AstraZeneca group of companies), ZD1839] increases the cellular uptake of radiolabelled epidermal growth factor (EGF). We investigated gefitinib treatment combined with astatine-211 EGF targeting in vitro using two cell lines expressing high levels of EGFR: A431 (sensitive to gefitinib) and U343MGaCl2:1 (resistant to gefitinib). In both cell lines, the uptake of 211At-EGF was markedly increased by concomitant treatment with gefitinib. Survival was investigated using both a clonogenic survival assay and a cell growth assay. Combined gefitinib and 211At-EGF treatment reduced the survival of U343 cells 3.5-fold compared with 211At-EGF alone. In A431 cells, 211At-EGF treatment resulted in very low survival, but combined treatment with gefitinib increased the survival by about 20-fold. These results indicate that combined treatment with gefitinib might increase the effect of ligand-mediated radionuclide therapy in gefitinib-resistant tumours and decrease the effect of such therapy in gefitinib-sensitive tumours.

Antineoplastic Agents↗
PubMed2001

Selective targeting of tumour neovasculature by a radiohalogenated human antibody fragment specific for the ED-B domain of fibronectin.

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.

Animals↗
PubMed1982

The specific inhibition of cellular clonogenic proliferation using 211At labelled lectins and antibodies--I.

A monoclonal antibody with a broad anti-human leucocyte specificity, designated BK 19.45 and the plant lectin Concanavalin A have been labelled with the alpha-emitting cyclotron produced radiohalogen astatine-211. Both human and murine tumour cell lines and human leukemic bone marrow samples have been specifically labelled with these radioactive proteins. In all cases the amount of 211At bound to the cells is directly correlated with a decrease in cellular reproductive potential as shown by the ability of the cells to proliferate in a clonogenic assay. For the labelled monoclonal antibody experiments, the radiation dose needed to yield 37% cell survival, the D37 dose, may be achieved with an average of 12 211At atoms/cell.

Animals↗
PubMed1982

The in vivo fate of a 211At labelled monoclonal antibody with known specificity in a murine system.

A monoclonal antibody reactive against the human transferrin receptor has been labelled with the alpha and X ray emitting isotope Astatine 211. The labelling procedure does not affect the ability of the product to bind to the transferrin receptor on the human leukemic cell line HL60. Using a direct binding assay, 211At labelled antibody can be specifically inhibited from binding to its target cells by excess unlabelled antibody. Furthermore, the binding inhibition demonstrated in this system correlates to enhanced clonogenic survival of these cells, indicating that very few atoms of 211At/cell are required for cell death. Data obtained from labelled antibody injected into mice show that the labelled product in serum retains the ability to bind to HL60 cells in vitro, although tissue distributions of the injected activity implies that some of the radiolabel is lost from the protein. Despite this loss of label, preliminary experiments on the localization of labelled antibody to HL60 cells growing s/c in nude mice show that tumor tissue has a higher specific activity than all other tissues, other than blood, after 12 hours. This suggests that further work on the nature of label degradation in vivo is warranted in the context of potential therapeutic and diagnostic studies.

Animals↗
PubMed1990

Modeling of dose to tumor and normal tissue from intraperitoneal radioimmunotherapy with alpha and beta emitters.

Dose distributions for normal and tumor tissues from intraperitoneally administered radiolabeled antibodies have been calculated for 90-Yttrium (90Y), 131-Iodine (131I), and 211-Astatine (211At). The dose calculations use data on the activity of intraperitoneal fluid administered, the percent injected dose/gm uptake by tumor, biological half life, and a model for diffusion of antibody/radionuclide complex into peritoneal tissues. Calculations are performed for planar and hemispherical tumor shapes, ranging in size to establish the influence of geometry on dose distribution. Calculations for tumor geometry obtained from biopsies are also performed. When the activity is concentrated on or near the tumor surface, the maximum dose to a planar tumor for a 20 mci administration of 90Y is approximately 60 Gy, and falls rapidly to 50% of this value within 1 mm. However, for a hemispherical tumor, the dose is a maximum of 26 Gy, with an average of approximately 20 Gy. The surface dose from 131I (130 mci) is 240 Gy, and diminishes to 20 Gy in .05 cm in the planar case, whereas a hemispherical tumor receives a dose of 90 Gy over a large fraction of the volume, with the distal portions receiving 40 Gy. The surface dose for an administration of 70 mci of 211 At is 450 Gy and decreases to 50% of this value in 30 microns. Both surface geometry and tumor size are important determinants in the heterogeneity of tumor dose, as are the dose administered, antibody uptake, biodistribution, and residence time factors. These initial studies suggest that the size of disease which may be effectively treated is much less than the range of the particle emitted by radiolabeled antibodies. Furthermore, therapy is ultimately limited by the degree to which the antibody/radionuclide complex can diffuse and permeate the tumor.

Antibodies, Monoclonal↗
PubMed1996

[211At]methylene blue for targeted radiotherapy of human melanoma xenografts: dose fractionation in the treatment of cutaneous tumours.

3,7-(dimethylamino) phenazathionium chloride [methylene blue (MTB)] labelled with alpha-particle emitter astatine-211 (211At) selectively accumulates in melanoma cells due to an exceptionally high affinity of MTB to melanin, and proves to be a very effective agent in targeting radiotherapy for pigmented human melanoma grown in mice. This study aimed at a selection of the most advantageous [211At]MTB dose fractionation leading to irreversible regression of the treated lesions. Nude mice bearing subcutaneous human melanoma xenografts of either highly pigmented HX118 or poorly pigmented HX34 human melanoma were treated with [211At]MTB administered intravenously. The treatment was performed using three different schedules of [211At]MTB fractionation: a single large dose, five fractions delivered sequentially every 48 h and two to five fractions given with a mean frequency of one per week. The effectiveness of [211At]MTB treatment was assessed by determination of the growth rate of cutaneous tumours and length of time between tumour implantation and killing of moribund mice. [211At]MTB applied with a mean frequency of one fraction per week appeared to be the most efficient treatment for highly pigmented HX118 melanomas. Its effectiveness was dependent on [211At]MTB activity used per fraction and the size of the cutaneous tumours at the beginning of the treatment. A total dose of [211At]MTB seemed of less importance. An irreversible regression of the lesions was achieved. Poorly pigmented cutaneous melanoma xenografts were affected most significantly by [211At]MTB applied as five fractions given every 48 h. The treatment caused a temporary inhibition of tumour growth after which the lesions regained the control growth rate. These and previous results suggest that [211At]MTB could successfully control the growth of already formed lesions of pigmented melanoma, as well as prevent metastatic spread of the tumour, provided an appropriate fractionation régime of the radiolabelled compound is employed.

Animals↗
PubMed1996

211At-methylene blue for targeted radiotherapy of disseminated melanoma: microscopic analysis of tumour versus normal tissue damage.

The present stage of our preclinical investigations of targeted radiotherapy for melanoma with 3,7-(dimethylamino)phenazathionium chloride [methylene blue (MTB)] labelled with astatine-211 (211At), an alpha-particle emitter, concerns toxicity of the treatment, as well as macro- and microscopic evaluation of its efficacy. Fragments of two human melanoma xenografts, pigmented HX118 and non-pigmented HX34 (used as a control), were implanted s.c. into nude mice subsequently treated with two doses of 211At-MTB injected i.v. Alterations in tumour growth rate were related to microscopic damage caused by 211At-MTB to the lesions, as determined by light microscopy using histopathological techniques. 211At-MTB-dependent growth inhibition of pigmented melanoma occurred either instantly or as a gradual reduction in the tumour growth rate. At a later stage, lesions that ceased to grow immediately consisted of quiescent, heavily pigmented tumour cells, as well as advanced fibrosis, and were extensively infiltrated by melanin-laden phagocytes. Large, unresorbed and often calcified necrotic deposits characterised the tumours responding gradually to the treatment. 211At-MTB remained non-toxic in normal organs. Only a relative number of small lymphocytes in the groin lymph nodes in a minority of animals was temporarily reduced, most often in conjunction with the treatment of pigmented tumours. The data demonstrated a high therapeutic effectiveness of 211At-MTB towards pigmented melanoma at the expense of negligible injury to normal tissues, and revealed that the macroscopic determination of tumour growth rate often underestimated an efficacy of the applied treatment.

Animals↗