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PubMed2005

Optimisation study of alpha-cyclotron production of At-211/Po-211g for high-LET metabolic radiotherapy purposes.

The production of no-carrier-added (NCA) alpha-emitter (211)At/(211g)Po radionuclides for high-LET targeted radiotherapy and immunoradiotherapy, through the (209)Bi(alpha,2n) reaction, together with the required wet radiochemistry and radioanalytical quality controls carried out at LASA is described, through dedicated irradiation experiments at the MC-40 cyclotron of JRC-Ispra. The amount of both the gamma-emitter (210)At and its long half-lived alpha-emitting daughter (210)Po is optimised and minimised by appropriate choice of energy and energy loss of alpha particle beam. The measured excitation functions for production of the main radioisotopic impurity (210)At-->(210)Po are compared with theoretical predictions from model calculations performed at ENEA.

Astatine↗

PubMed2004

The effects of proton exposure on neurochemistry and behavior.

Future space missions will involve long-term travel beyond the magnetic field of the Earth, where astronauts will be exposed to radiation hazards such as those that arise from galactic cosmic rays. Galactic cosmic rays are composed of protons, alpha particles, and particles of high energy and charge (HZE particles). Research by our group has shown that exposure to HZE particles, primarily 600 MeV/n and 1 GeV/n 56Fe, can produce significant alterations in brain neurochemistry and behavior. However, given that protons can make up a significant portion of the radiation spectrum, it is important to study their effects on neural functioning and on related performance. Therefore, these studies examined the effects of exposure to proton irradiation on neurochemical and behavioral endpoints, including dopaminergic functioning, amphetamine-induced conditioned taste aversion learning, and spatial learning and memory as measured by the Morris water maze. Male Sprague-Dawley rats received a dose of 0, 1.5, 3.0 or 4.0 Gy of 250 MeV protons at Loma Linda University and were tested in the different behavioral tests at various times following exposure. Results showed that there was no effect of proton irradiation at any dose on any of the endpoints measured. Therefore, there is a contrast between the insignificant effects of high dose proton exposure and the dramatic effectiveness of low dose (<0.1 Gy) exposures to 56Fe particles on both neurochemical and behavioral endpoints.

Animals↗

PubMed2005

The involvement of key DNA repair pathways in the formation of chromosome rearrangements in embryonic stem cells.

It is vital that embryonic stem (ES) cells, which give rise to the diverse tissues of the mature organism, maintain genetic stability. To understand mechanisms for the prevention and causation of chromosomal instability, we have used spectral karyotyping (SKY) to analyse ES cells from wild-type and repair-gene knockout mice. We chose cells deficient in Ku70 (DNA end joining), Xrcc2 (gene conversion), Ercc1 (single-strand annealing) and Csb (transcription-coupled repair) to represent potentially-important DNA repair pathways, plus an Xpc-deficient line to examine loss of global nucleotide excision repair (NER). Spontaneous and radiation (X-ray or alpha-particle)-induced chromosome changes were assessed to measure the influence of different levels of damage severity on response. We show that most repair pathways (except for global NER) protect against chromosome changes induced by ionizing radiations, while only homology-dependent pathways protect against spontaneous chromosomal change in ES cells. However, for a given level of damage, the prevalence of different types of changes alters in the different repair-deficient lines. Thus, loss of Ercc1, Csb or Ku70 leads to increased fragment formation, but loss of Xrcc2 promotes exchanges between chromosomes. Strikingly, we found that loss of the Csb gene function specifically protects ES cells from complex exchanges, suggesting a role for transcription-associated events in complex exchange formation.

Animals↗

PubMed2006

Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(ab')2.

PURPOSE: To elucidate the therapeutic efficacy of alpha-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the alpha-particle emitter Astatine-211 (211At) labeled to the mAb MX35 F(ab')2. METHODS AND MATERIALS: Animals were inoculated intraperitoneally with approximately 1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq 211At-MX35 F(ab')2 (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq 211At-Rituximab F(ab')2 (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF). RESULTS: When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq (211)At-MX35 F(ab')2, respectively, the specific energy to irradiated cell nuclei varying between approximately 2 and approximately 400 Gy. CONCLUSION: As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is approximately 100 kBq (211)At-MX35 F(ab')2. MCP was most consistent with the TFF when assuming a diffusion depth of 30 mum of the mAbs in the tumors.

Animals↗

PubMed2005

Controlling gas-phase reactions for efficient charge reduction electrospray mass spectrometry of intact proteins.

Charge reduction electrospray mass spectrometry (CREMS) reduces the charge states of electrospray-generated ions, which concentrates the ions from a protein into fewer peaks spread over a larger m/z range, thereby increasing peak separation and decreasing spectral congestion. An optimized design for a CREMS source is described that provides an order-of-magnitude increase in sensitivity compared to previous designs and provides control over the extent of charge reduction. Either a corona discharge or an alpha-particle source was employed to generate anions that abstract protons from electrosprayed protein cations. These desired ion/ion proton transfer reactions predominated, but some oxidation and ion-attachment reactions also occurred, leading to new peaks or mass-shifted broader peaks while decreasing signal intensity. The species producing these deleterious side-reactions were identified, and conditions were found that prevented their formation. Spectrometer m/z biases were examined because of their effect upon the signal intensity of higher m/z charge-reduced protein ions. The utility of this atmospheric pressure CREMS was demonstrated using a cell lysate fraction from E. coli. The spectral simplification afforded by CREMS reveals more proteins than are observed without charge reduction.

Electrochemistry↗

PubMed2004

Sequential extraction of 226Ra in sediments from an estuary affected historically by anthropogenic inputs of natural radionuclides.

Riverbed sediments from an estuary historically affected by wastes discharged by several phosphate fertiliser plants and enriched in uranium-series radionuclides were operationally speciated using a Tessier-based method. In each selective fraction the (226)Ra content was determined by alpha-particle spectrometry after radiochemical isolation and electrodeposition onto stainless steel planchets. These studies were performed in (226)Ra-polluted estuarine sediments collected one year after anthropogenic discharges had ceased in order to obtain useful information about the operational forms in which this radionuclide remains associated with the sediments at this time. The results obtained revealed that one year after (226)Ra inputs had stopped, the radionuclide was associated mostly with the more refractory forms. Consequently, it is possible to foresee little potential remobilisation of (226)Ra contamination from sediments to the aqueous phase in the future under normal environmental conditions.

Chemical Industry↗

PubMed2005

Pretargeted radioimmunotherapy in tumored mice using an in vivo 212Pb/212Bi generator.

OBJECTIVE: Pretargeting is the concept that combines optimal delivery of the antibody and rapid capture and elimination of the radioactivity. In this study, we evaluated the potential of antibody pretargeting to enable the tumor-targeting (212)Pb for in vivo generation of (212)Bi for alpha particle radiotherapy. METHODS: The (212)Pb/(212)Bi chelate of DOTA-biotin, as well as their gamma-emitting analogues, (203)Pb and (205)Bi, was prepared and characterized. The radiolabeled compounds were injected in animals for evaluation of tumor targeting and normal tissue uptake and retention. In the pretargeting protocol, injection of 400 microg of NR-LU-10 antibody-streptavidin conjugate was given at t = 0 h, then 100 microg of N-acetyl-galatosamine-biotin clearing agent was injected at t = 20-24 h; finally, 1 microg of (212)Pb/(212)Bi-DOTA-biotin was injected 6 h later. RESULTS: Both (203)Pb and (205)Bi-DOTA-biotin were stable for at least 4 days in the different challenging solutions including PBS, 10 mM DTPA and serum. Contrary to its gamma-emitting analogues, radiolabeled (212)Pb-DOTA-biotin was not stable. There was greater than 30% of free (212)Bi released 4 h after (212)Pb-labeled DOTA-biotin. The results of pretargeting protocol of (203)Pb and (205)Bi-DOTA-biotin showed that the tumor target reached 20% injected dose (ID)/g at 4 h postinjection and remained high for 5 days. The %ID/g in the whole blood and other nontarget organs was low after administration of labeled (203)Pb and (205)Bi-DOTA-biotin similar to the biodistribution of labeled DOTA-biotin alone. In the animals administered (212)Pb-DOTA-biotin, radioactivity in nontarget organs was low except the kidneys. The %ID/g in the kidney for (212)Bi was 14.5 at 2 h, higher than (212)Pb, but dropped to about 6% ID/g by 4 h. However, tumor uptake for (212)Pb and (212)Bi was >25% ID/g at 1 h postinjection and remained so through 24 h. CONCLUSIONS: Antibody pretargeting system with Mab-streptavidin, clearing agent and DOTA-biotin provides the potential of (212)Bi for solid tumor radiotherapy despite the release of (212)Bi after (212)Pb decay. Dosimetry calculations resulted in tumor dose at 93 rad/muCi and ratios of tumor to marrow and kidney at 386:1 and 12:1, respectively.

Animals↗

PubMed2006

In vitro cytotoxicity of 211At-labeled trastuzumab in human breast cancer cell lines: effect of specific activity and HER2 receptor heterogeneity on survival fraction.

INTRODUCTION: Radioimmunotherapy with anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab is a promising strategy for treating HER2-positive breast and ovarian carcinoma patients. The objective of this study was to determine the cytotoxic effectiveness of trastuzumab labeled with the 7.2-h half-life alpha-particle emitter 211At. METHODS: Experiments were performed on SKBr-3, BT-474 and the transfected MCF7/HER2-18 human breast carcinoma cell lines. Intrinsic radiosensitivity was determined after exposure to external beam irradiation. The cytotoxicity of 211At-labeled trastuzumab was measured by clonogenic assays. The distribution of HER2 receptor expression on the cell lines was measured using fluorescence-activated cell sorting. A pharmacokinetic (PK)/microdosimetric model was established to assess the effects of specific activity (SA), HER2 receptor expression and absorbed dose on survival fraction (SF). RESULTS: With external beam irradiation, the 2-Gy SF for BT-474, SKBr-3 and MCF7/HER2-18 cells was 0.78, 0.53 and 0.64 Gy, respectively. Heterogeneous HER2 expression was observed, with a subpopulation of cells lacking measurable receptor (14.5%, SKBr-3; 0.34%, MCF-7/HER2; 1.73%, BT-474). When plotted as a function of activity concentration, SF curves were biphasic and inversely proportional to SA; however, when the model was applied and absorbed doses calculated, the SF curve was monoexponential independent of SA. Thus, the PK model was able to demonstrate the effects of competition between cold and labeled mAb. These studies showed that the relative biological effectiveness of 211At-labeled trastuzaumab was about 10 times higher than that of external beam therapy. CONCLUSION: These in vitro studies showed that 211At-labeled trastuzumab mAb is an effective cytotoxic agent for the treatment of HER2-positive tumor cells. The SA of the labeled mAb and the homogeneity of HER2 receptor expression are important variables influencing the efficiency of cell killing.

Antibodies, Monoclonal↗

PubMed2004

Radioiodine and 211At-labeled guanidinomethyl halobenzoyl octreotate conjugates: potential peptide radiotherapeutics for somatostatin receptor-positive cancers.

Derivatives of the somatostatin analogues octreotide and octreotate labeled with radioiosotopes are used in the diagnosis and therapy of somatostatin receptor (SSTR)-positive tumors. A method has been devised to synthesize {N-(4-guanidinomethyl-3-iodobenzoyl)-Phe1-octreotate (GMIBO). Receptor binding assay and scatchard analysis yielded a Kd of 4.83 +/- 0.19 nM for this peptide. Derivatives of this peptide labeled with radioiodine ([*I]GMIBO) and the alpha-particle-emitting radiohalogen 211At N-(3-[211At]astato-4-guanidinomethylbenzoyl)-Phe1-octreotate; [211At]AGMBO} were prepared in a single step from a tin precursor in radiochemical yields of 30-35% and 15-20%, respectively. Paired-label internalization assays performed with the SSTR-positive D341 Med human medulloblastoma cell line demonstrated that [125I]GMIBO and [211At]AGMBO were specifically internalized 20-40% more than Nalpha-(1-deoxy-D-fructosyl)-[131I]I-Tyr3-octreotate ([131I]I-Glu-TOCA), the radioiodinated octreotide derivative previously shown to exhibit maximum internalization in this cell line. Uptake of [131I]GMIBO in D341 Med subcutaneous xenografts in a murine model (8.34 +/- 1.82 versus 8.10 +/- 2.23% ID/g at 1h) and SSTR-expressing normal tissues was comparable to that of [125I]I-Glu-TOCA and was shown to be specific. However, the uptake of [131I]GMIBO also was substantially higher in liver (16.9 +/- 3.15 versus 1.39 +/- 0.45% ID/g at 1 h) and in kidneys (44.33 +/- 6.47 versus 3.44 +/- 0.68% ID/g at 1h) compared to that of [125I]I-Glu-TOCA. These data suggest that these novel peptide conjugates retain their specificity for SSTR both in vitro and in vivo; however, because of their higher accumulation in normal tissues they would be best applied in settings amenable to loco-regional administration such as medulloblastoma neoplastic meningitis.

Animals↗

PubMedDate not supplied

LiF:Mg,Ti (MTT) TL detectors optimised for high-LET radiation dosimetry.

The properties of LiF:Mg,Ti (distributed as, e.g., TLD-100 or MTS-N), the most frequently used thermoluminescent detector, have been optimised for measurements of sparsely ionizing radiation (gamma rays), typically encountered in radiation protection or clinical dosimetry. However, these detectors need also to be applied in conditions of mixed-field dosimetry with a high-LET component, such as those encountered in heavy ion beams or in space. At the Institute of Nuclear Physics in Kraków a new type of LiF:Mg,Ti detector (named MTT) has been recently developed through modification of its dopant composition. This composition is intended to increase the detection efficiency after a dose of high-LET radiation. The concentration of dopants in the MTT material is: CMg=50 ppm, and CTi=120 ppm, i.e. about a three times less of magnesium and about 10 times more of titanium content, compared with the standard MTS-N. The MTT TL detectors feature an increased relative efficiency to high-LET radiation, which for 5 MeV alpha-particles is about twice that of standard LiF:Mg,Ti. The response of MTT detectors has been studied in charged particle beams of the HIMAC accelerator in Chiba, Japan and in Dubna, Russia. The main foreseen application of MTT detectors are dose measurements in space. The dose after high-LET exposure can be estimated from the difference of the response of MTS and MTT detectors. In the near future MTT detectors will be applied in the "Matroshka" experiment. Within this experiment a specially constructed human phantom will be exposed in free space (outside the International Space Station) for 1 year. The phantom will incorporate a few thousand measuring points enabling radiation doses to particular organs to be determined.

Extraterrestrial Environment↗

PubMed2004

Compounds of 6Li and natural Li for EPR dosimetry in photon/neutron mixed radiation fields.

Formates and dithionates of 6Li, enriched and 7Li in natural composition of Li offer a possibility to measure the absorbed dose from photons and thermal neutrons in a mixed radiation field for instance at a boron neutron capture therapy (BNCT) facility. Tests with formates and dithionates of enriched 6Li and lithium compounds with natural composition have been performed at the BNCT facility at Studsvik, Sweden. Irradiations have been performed at 3 cm depth in a Perspex phantom in a fluence rate of thermal neutrons 1.8 x 10(9) n cm(-2) s(-1). The compounds were also irradiated in a pure X-ray field from a 4MV linear accelerator at 5 cm depth in a phantom with accurately determined absorbed doses. The signal intensity and shape was investigated within 3 h after the irradiation. A single line spectrum attributed to the CO2- radical was observed after irradiation of lithium formate. An increase in line width occurring after neutron irradiation in comparison with photon irradiation of the 6Li sample was attributed to dipolar broadening between CO2- radicals trapped in the tracks of the alpha particles. A spectrum due to the SO3- radical anion was observed after irradiation of lithium dithionate. The signal amplitude increased using the 6Li in place of the Li with natural composition of isotopes, in studies with low energy X-ray irradiation. Due to the decreased line width, caused by the difference in g(N) and I between the isotopes, the sensitivity with 6Li dithionate may be enhanced by an order of magnitude compared to alanine dosimetry. After comprehensive examination of the different combinations of compounds with different amounts of 6Li and 7Li regarding dosimetry, radiation chemistry and EPR properties these dosimeter material might be used for dose determinations at BNCT treatments and for biomedical experiments. Interesting properties of the radical formation might be visible due to the large difference in ionization density of neutrons compared to photons.

Alanine↗

PubMed1961

Radiation inhibition of amino acid uptake by Escherichia coli.

The inhibition of macromolecular synthesis in Escherichia coli by ionizing radiation has been investigated. The survival of the ability to incorporate arginine, leucine, isoleucine, histidine, uracil, and glucose after various doses of gamma radiation, deuteron and alpha particle bombardment has been measured. All amino acids are incorporated by processes which show the same radiation sensitivity. The sensitivity of uracil corresponds to a volume which is roughly spherical, of radius about 160A, whereas the amino acids possess sensitive regions which are long and thin in character. The uptake of glucose is concerned with a smaller, roughly spherical unit. The possible identification of the radiation-sensitive targets with cellular constituents is discussed. The long thin character observed for amino acids suggests that the sensitive region affected by radiation is an unfolded form of a ribosome, or alternatively a long nucleic acid molecule. For uracil the sensitive region fits with a 70S ribosome, while for glucose a smaller particle would fit the data.

Amino Acids↗

PubMedDate not supplied

Thorium-dioxide--induced pharyngeal hemorrhage.

Thorium dioxide, a producer of alpha particle radiation, was used in the United States from 1930 to 1950 for carotid and cerebral angiography. Cervical thorium dioxide granuloma is a well-recognized sequela of extravasation of this material near the carotid bifurcation. Radical neck dissection to remove the granuloma for aesthetic and functional reasons may lead to massive postoperative hemorrhage if a patent, but radiation-weakened, carotid artery is present. Additionally, hemorrhage may occur spontaneously because of pharyngeal necrosis or following infection of a pharyngeal biopsy site. The case described illustrates that life-threatening, thorium-dioxide--induced pharyngeal hemorrhage may occur even with an occluded carotid system. The bleeding site may go unrecognized, and laryngopharyngectomy with radical neck debridement may be required for hemostasis. Extension of an infection into the retroesophageal space and thoracic inlet requires exteriorization of the entire neck wound to prevent placing the great vessels of the superior mediastinum at risk for rupture. Spontaneous rupture of the aorta may occur due to thorium-dioxide--induced necrosis of its wall.

Arterial Occlusive Diseases↗

PubMed2001

Concentrations and activity ratios of uranium isotopes in the groundwater of the Okchun Belt in Korea.

Groundwater samples obtained from the Okchun Belt in Korea were separated into particulate and filtered fraction using a 0.45 microm membrane filter and concentrations and activity ratios of uranium isotopes in the fractions were determined by chemical separation and alpha-spectrometric measurements. Most of the uranium isotopes in the groundwater were found in the filtered water. Only less than 1% of the total uranium was detected in the particulate fraction. The concentrations and activity ratios of uranium isotopes in the groundwater measured in this study were variable, depending upon sampling site. Owing to a rapid material exchange between the subterranean hot waters and the rock strata, the concentrations of 238U in the groundwater in the hot spring area were found to be about four times higher than those elsewhere. Because of the alpha-particle recoil effect, the activity ratios of 234U/238U in the groundwater taken at "cold" spring sites were variable within the range 1.20 to 3.58, depending on the residence time of the groundwater. In the hot spring area, the activity ratios of 234U/238U were close to the equilibrium value (1.10 +/- 0.07) due to rapid erosion of the rock strata by the hot spring water.

Environmental Monitoring↗

PubMed2002

An overview of instrumentantion for measuring radon in soil gas and groundwaters.

Instruments for the measurements of radon and its decay products in earthquake research are based mostly on the detection of alpha particles. The devices and methods used, depend on whether the techniques measure radon or radon decay products, and the duration of the measurements, of which there are three types: (i) grab or instantaneous; (ii) integrating; and (iii) continuous. Other criteria used in the design of these instruments are field measurements applicability. portability. convenience and reliability. With the recent increased demand for radon and radon decay products measurements, instruments development has focused on the design of appropriate devices for short-term measurements, as well as on more complex and sophisticated instruments for long-term measurements used in radon research for geophysical, geochemical and hydrological studies.

Disasters↗

PubMed2000

Induction of DNA double-strand breaks in mammalian cells and yeast.

Induction of DNA double-strand breaks (dsb) and their distribution are dependent on the energy deposition pattern within the cell nucleus (physical structure) and the ultrastructure of the chromosomes and its variation by the cell cycle and gene activities (biological structure). For electron radiation very similar RBE-values are observed for mammalian and yeast cells (AlK, 1.5 keV, 15 keV/micrometer: 2.6 in mammalian cells and 2.2 in yeast; CK 0.278 keV, 23 keV/micrometer: approx. 2.5 in mammalian cells and 3.8 in yeast). In contrast, the RBE-values for the induction of dsb of 4He2+ and light ions in the LET range from about 100 keV/micrometer up to 1000 keV/micrometer are significantly higher for yeast cells compared to mammalian cells. For example, the RBE-value of alpha-particles (120 keV/micrometer) is about 1.2 for mammalian cells whereas for yeast the RBE-value is about 2.5. The yeast chromatin has less condensed fibres compared with mammalian cells. Since a single CK photoelectron can induce only one dsb, the different condensation of the mammalian and yeast chromatin has no influence. However, particles may induce more than one dsb when traversing a chromatin fibre. The probability for the induction of closely neighboured dsb is higher the more condensed the chromatin fibres are. Since small DNA fragments (50 bp up to several kbp) are lost by standard methods of lysis, the underestimation of dsb yields increases with fibre condensation, which is in accordance with the observes dsb yields in mammalian cells and yeast. In order to obtain relevant yields of dsb (and corresponding RBE-values) the measurement of all DNA fragments down to about 50 bp are needed.

DNA Damage↗

PubMed1997

Clinical dosimetry of an epithermal neutron beam for neutron capture therapy: dose distributions under reference conditions.

PURPOSE: The aim of this study was to asses the dose distribution under reference conditions for the various dose components of the Petten clinical epithermal neutron beam for boron neutron capture therapy (BNCT). METHODS AND MATERIALS: Activation foils and a silicon alpha-particle detector with a 6Li converter plate have been used for the determination of the thermal neutron fluence rate. The gamma-ray dose rate and the fast neutron dose rate have been determined using paired ionization chambers. Circular beam apertures of 8, 12 and 15 cm diameters have been investigated using a 15 x 15 x 15 cm3 solid polymethyl-methacrylate phantom, a water phantom of the same dimensions and a 30 x 30 x 30 cm3 water phantom at various phantom to beam-exit distances. RESULTS: The effect of phantom to beam-exit distance could be modeled using an inverse square law with a virtual source to beam-exit distance of 3.0 m. At a reference phantom to beam-exit distance of 30 cm, three-dimensional dose and fluence distributions of the various dose components have been determined in the phantoms. The absolute thermal neutron fluence rate at a reference depth of 2 cm in the 15 cm water phantom increased by 43% when the field size was increased from 8 to 15 cm. Simultaneously the gamma-ray dose rate increased by 46% while the fast neutron dose rate increased by only 5%. CONCLUSION: A reference treatment position at 30 cm from the beam exit allows convenient patient positioning with a relatively small increase in irradiation time compared to positions very close to the beam-exit. A more homogeneous distribution of thermal neutrons over a target volume, a higher absolute thermal neutron fluence rate and a lower contribution of the fast neutron dose to the total dose will result in improved treatment plans when using a 12 cm or 15 cm field compared to a 8 cm field. The dose distributions will be used as benchmark data for treatment planning systems for BNCT.

Boron Neutron Capture Therapy↗

PubMed1999

Radiotoxicity of systemically administered 211At-labeled human/mouse chimeric monoclonal antibody: a long-term survival study with histologic analysis.

PURPOSE: The antitenascin human/mouse chimeric monoclonal antibody labeled with the alpha-particle-emitting radionuclide 211At is of interest as an endoradiotherapeutic agent for the treatment of brain tumors. To facilitate the investigation of 211At-labeled chimeric 81C6 in patients, the long-term radiotoxicity of this radiopharmaceutical has been evaluated. METHODS AND MATERIALS: Antibody labeling was performed using N-succinimidyl 3-[211At]astato-benzoate. After an initial dose-finding experiment, a second toxicity study was carried out at 4 dose levels in groups of 30 nonthyroid blocked B6C3F1 mice per group (15 males, 15 females). Male mice received either saline or 15-81 kBq/g and females received either saline or 16-83 kBq/g of 211At-labeled antibody. Ten animals (5 males, 5 females) were followed for 6 months and the remainder for 1 year. RESULTS: The lethal dose in 10% of animals (LD10) for 211At-labeled chimeric 81C6 was 46 kBq/g in females and 102 kBq/g in males. Toxic effects--perivascular fibrosis of the intraventricular septum of the heart, bone marrow suppression, splenic white pulp atrophy, and spermatic maturational delay--generally were confined to a few animals receiving the highest doses of labeled antibody. CONCLUSIONS: The LD10 of 211At-labeled chimeric 81C6 in this mouse strain was about half that of [211At]astatide. These results establish the preclinical maximum tolerated dose of 211At-labeled chimeric 81C6 and define in the mouse the target organs for toxicity. These studies will be useful for determining starting doses for clinical studies with 211At-labeled chimeric 81C6.

Animals↗