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PubMed1997

Advantage of yttrium-90-labeled over iodine-131-labeled monoclonal antibodies in the treatment of a human lung carcinoma xenograft.

BACKGROUND: The purpose of this investigation was to compare the therapeutic effectiveness of yttrium-90 (90Y)-labeled monoclonal antibodies (MoAbs) with iodine-131 (131I)-labeled MoAbs delivered to human tumor xenografts at their maximum tolerated doses (MTD). METHODS: Nude mice bearing size-matched human lung adenocarcinoma xenografts (Calu-3) with mean tumor dimensions of approximately 0.8 cm received intravenous injections of the MTD of either 90Y- or 131I-labeled MoAbs. The mice received 125 microCi of 90Y-RS11 or 90Y-RS7, or 300 microCi of 131I-RS11 or 131I-RS7. Tumor size was measured weekly. Body weight and blood counts were monitored to measure toxicity. RESULTS: The calculated average radiation doses delivered to tumors in mice treated with 90Y-RS11 and 90Y-RS7 were 3578 and 3787 centigray (cGy), respectively, versus 1264 and 1368 cGy for 131I-RS11 and 131I-RS7, respectively. These values were calculated taking into consideration the tumor size-dependent absorbed fractions for the beta particles of both radioisotopes. The calculated radiation doses absorbed in the tumor correlated with the tumor responses observed. Mean tumor volume decreases at nadir were 66% and 87% after 90Y-RS11 and 90Y-RS7 therapy, respectively, with 15 of 30 mice treated with either MoAb having complete regression of their tumors. In contrast, only mean stable disease was observed with the 131I MoAb treatments. CONCLUSIONS: The results demonstrate the superiority of 90Y-labeled MoAbs over conventionally labeled 131I-labeled MoAbs for therapy in this model. The fact that a substantial percentage of complete remissions was achieved with 90Y-labeled MoAbs suggests a considerable radiosensitivity of the tumor studied, and supports the suitability of choosing this tumor type as an attractive target for future clinical radioimmunotherapy.

Animals↗
PubMed1997

Can occult metastases be treated by radioimmunotherapy?

BACKGROUND: Tumor lesions in the millimeter (mm) range may escape detection with nuclear medicine imaging methods (including single photon emission computed tomography [SPECT]) using radiolabeled monoclonal antibodies (MoAbs). We hypothesized that these lesions still could receive a potentially therapeutic radiation absorbed dose, and therefore should be treated, despite the lack of detection. METHODS: To simulate this situation, 2-mm beads (0.004 mL) containing approximately 1.15 microCi of iodine-131 (131I) were used. The beads were placed centrally in a 1200-mL liver phantom containing approximately 3 mCi of 131I. The resultant activity concentration on the beads was approximately 288 microCi/mL compared with approximately 2.5 microCi/mL in the phantom, corresponding to a maximum tumor uptake of approximately 0.3% injected dose per gram (%ID/g) if 100 mCi of 131I-labeled immunoglobulin G were administered. The phantom, containing the beads, was imaged by both planar and SPECT techniques at hypothetical Day 1 (time of maximum tumor uptake) and at hypothetical Day 7 to examine the improved target-to-nontarget ratio over time. In addition to imaging the beads, the radiation absorbed dose to the simulated lesions from the beta component emissions of 131I was calculated using absorbed fractions based on Berger's point kernels. RESULTS: Regardless of the conditions used, the beads could not be observed by either planar or SPECT imaging. However, the radiation-absorbed dose to the simulated lesion was calculated to be as high as approximately 6200 centigray (cGy), with an average dose rate of approximately 89.5 cGy/hour. CONCLUSIONS: This simulation demonstrates that a relatively high absorbed dose and dose rate can be delivered to mm-sized lesions not observed by conventional nuclear imaging methods, and that these lesions should be considered for radioimmunotherapy with 1311 MoAbs. However, for micrometastases of <1 mm, other radionuclides with shorter path length beta particles than 131I, Auger electrons, or alpha particles should be considered.

Humans↗
PubMed2000

Radiolabeling brachytherapy sources with Re-188 through chelating microfilms: stents.

Rhenium-188 (Re-188, T(1/2) = 17 h) emits beta particles (E(max) = 2. 12 MeV) having an ideal range for intravascular brachytherapy and certain cancer brachytherapies. Re-188 was attached to metal wafers and stents via a chelating microfilm, and these brachytherapy sources characterized in vitro and in vivo. To prepare the sources, a siloxane film containing reactive amines was plasma deposited on the metal, a chelating microfilm conjugated to the amines, and the chelating microfilm used to attach Re-188. Re-188 was selectively bound to materials coated with the chelating microfilm. Binding correlated with the amount of radionuclide used. Wafers (1 cm(2)) bound up to 62.9 MBq (1.7 mCi) of Re-188 with yields generally near 30%. Stents bound up to 26.6 MBq (720 microCi). Typically, stents were labeled to bind 4-12 MBq and deposit 10-30 Gy at 2 mm in the arterial wall. In phantom studies, the longer nitinol stents deposited doses of 2.3 Gy/MBq (0.085 Gy/microCi), while shorter stainless steel stents deposited 4.62 Gy/MBq (0.171 Gy/microCi). After placement in arteries of pigs, only the Re-188-stents were detected by scintigraphy at times up to 24 h. Scintigraphy did not detect activity in other organs. Blood sampling (0.1-24 h) detected maximum radioactivity (up to 388 cpm/mL/100micro Ci) at 6 h. We conclude that on-demand radiolabeling of stents and other brachytherapy sources with Re-188 can be performed routinely.

Biocompatible Materials↗
PubMed2000

Parity violation and the evolution of biomolecular homochirality.

Parity violation at the level of terrestrial biopolymers, as seen in proteins, DNAs, and RNAs, and parity violation at the level of nuclear processes, as evident in longitudinally polarized beta-particles and parity-violating energy differences (PVEDs), are discussed and their fundamental importances are emphasized. Attempts to find a causal connection between the unique homochirality of biopolymers and parity violation at the nuclear level, and speculations that the former is a consequence of the latter, are reviewed. Consideration of all lines of evidence leads to the conclusion that there is no substantiation for such a causal connection, and that the two levels of parity violation are entirely independent of each other.

Crystallization↗
PubMed1993

Strontium-89--precursor targeted therapy for pain relief of blastic metastatic disease.

Strontium-89 is a radioactive calcium analog that provides an energetic beta particle for radiation therapy of osteoblastic disease. Strontium-89 is used as palliative therapy with the primary goal being pain relief. More than 500 patients with painful blastic metastatic disease were treated at University of Kansas Medical Center since the initiation of the first clinical trial there 15 years ago. Most patients have had metastatic prostate cancer to bone or breast cancer, as these tumors are commonly associated with bone pain as their primary clinical management problem. Improvement (decrease in pain, increase in physical activity level) was noted in 80% of patients with prostate carcinoma and 81% of patients with metastatic breast cancer to bone. Marrow toxicity levels were acceptable. The therapy can be repeated at 3-month intervals. Strontium-89 is a safe and effective systemic therapy for painful blastic metastatic disease. There is no longer any reason why the vast majority of persons with painful blastic metastatic disease should continue to hurt.

Bone Neoplasms↗
PubMed1994

Radiation dosimetry for radioimmunotherapy. An overview of current capabilities and limitations.

BACKGROUND. The two major uncertainties associated with absorbed dose calculations involve: (1) measurement errors from assessment of radioactivity in specific organs and tissues by direct counting; and (2) application of standard anthropomorphic and biokinetic models for dose assessment. Uncertainties in direct counting result from the inherent difficulty of measuring radioactivity inside the body. Although the system recommended by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine provides a general framework and conceptual basis for the dosimetry of administered radiopharmaceuticals, it does not provide complete methods for assessing some of the more important quantities of interest in radioimmunotherapy, such as dose to tumors and descriptions of spatial dose distributions within tissues. Current MIRD anthropomorphic models are only crude representations of the human body. Generalized biokinetic models used in the MIRD system may vary considerably from the actual biokinetics of radiolabeled compounds in the body. This review describes limitations of the present MIRD system for radioimmunotherapy; they include assumptions used in treatment planning and the lack of specific methods for tumor dosimetry, multi-cellular dosimetry, microdosimetry, small animal dosimetry, and uncertainty analysis. CONCLUSIONS. Treatment planning for radioimmunotherapy requires patient-specific organ models and customized biokinetic parameters. Improvements are also needed in marrow dosimetry to account for the amount and distribution of red marrow relative to that found in adjacent source regions, skeletal structures, and circulating blood. Simplified assumptions with regard to the locally absorbed fraction of beta-particle energy in tissues adjacent to source regions should not be used when depth-dose profiles are needed; for example, radiation absorbed doses to intestinal walls should be calculated over the entire mass of tissue or described by absorbed-dose distributions. Additional research is needed to develop improved measurement techniques and computational methods to assess more accurately internal dose distributions within tumors and normal tissues.

Humans↗
PubMedDate not supplied

A gene therapy/targeted radiotherapy strategy for radiation cell kill by.

BACKGROUND: Although [131I]meta-iodobenzylguanidine (MIBG) is currently one of the best agents available for targeted radiotherapy, its use is confined to a few neural crest derived tumours which accumulate the radiopharmaceutical via the noradrenaline transporter (NAT). To determine whether this drug could be used for the treatment of non-NAT expressing tumours following genetic manipulation, we previously showed that plasmid mediated transfection of NAT into a non-NAT expressing glioblastoma cell line, UVW, endowed the host cells with the capacity to actively accumulate [131I]MIBG. We now present data defining the conditions required for complete sterilisation of NAT transfected cells cultured as multicellular spheroids and treated with [131I]MIBG. METHODS: NAT transfected UVW cells, grown as monolayers and spheroids, were treated with various doses of [131I]MIBG and assessed for cell kill by clonogenic survival and measurement of spheroid volume over time (growth delay). Spheroids were left intact for different time periods to assess the effect of radiation crossfire on cell death. RESULTS AND CONCLUSIONS: Total clonogen sterilisation was observed when the cells were grown as three-dimensional spheroids and treated with 7 MBq/ml [131I]MIBG. The added benefit of radiation crossfire was demonstrated by the improvement in cell kill achieved by prolongation of the maintenance of [131I]MIBG treated spheroids in their three-dimensional form, before disaggregation and clonogenic assay. When left intact for 48 h after treatment, spheroid cure was achieved by exposure to 6 MBq/ml [131I]MIBG. These results demonstrate that the efficiency of cell kill by [131I]MIBG targeted therapy is strongly dependent on beta-particle crossfire irradiation. This gene therapy/targeted radiotherapy strategy has potential for [131I]MIBG mediated cell kill in tumours other than those derived from the neural crest.

3-Iodobenzylguanidine↗
PubMed1985

Quantitative analyses of axonal endings in the central nucleus of the inferior colliculus and distribution of 3H-labeling after injections in the dorsal cochlear nucleus.

Quantitative analyses of electron microscopic (EM) autoradiographs were used to identify the afferents from the dorsal cochlear nucleus in the central nucleus of the inferior colliculus (IC) in the cat. In order to localize the sources of radioactivity, material from axonal transport experiments was analyzed by means of a hypothetical grain procedure which takes the cross-scatter of beta particles into account. Measurements of the synaptic vesicles in axonal endings and a cluster analysis were used to identify different groups of endings. In order to determine which types of endings arise in the dorsal cochlear nucleus, axonal endings labeled after axonal transport and unlabeled endings were characterized and compared to the groups defined by the cluster analysis. Axonal endings with round synaptic vesicles were labeled with more than 2 grains/micron2 which was about 30% of the radioactivity in the central nucleus of the IC. This was six to seven times greater than if the radioactivity had been randomly distributed. Other tissue compartments usually had less radioactivity. Some myelinated and unmyelinated axons were labeled, but, as a group they had lower amounts of radioactivity than predicted by random labeling. In most cases, only low levels of activity were found in glial and postsynaptic structures. Five groups of axonal endings in the medial part of the central nucleus were identified by an analysis which clustered similar types of endings. The variance of the longest axis, the mean diameter, the variance of area, and the mean area of the synaptic vesicles were the variables most useful in distinguishing these five groups. Axonal endings with round synaptic vesicles were classified as either small, or large, or very large, while endings with pleomorphic vesicles were either large or small. Using measurements of the cross-sectional diameter of dendritic microtubules, samples of digitized axonal endings from normal and experimental cases were normalized and could be compared directly to the groups defined by the cluster analysis. Microtubules were 21.7 nm (+/- 1.6) in average diameter. After injections of 3H-leucine and/or proline in the dorsal cochlear nucleus, most of the labeled endings in the IC contained small, round vesicles (less than 47 nm in diameter) although a very small number of endings with large, round vesicles also were labeled.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Proliferative response of bystander cells adjacent to cells with incorporated radioactivity.

BACKGROUND: In a recent study, we showed that cells irradiated with gamma-rays stimulate cell growth of unirradiated (bystander) cells, when the two populations are co-cultured as a mixture. Direct cell-to-cell contact appears to be a prerequisite for the proliferative response of the bystander cells. The aim of the current work is to investigate the possible proliferative bystander effects caused by intracellular irradiation with incorporated radionuclides, specifically the short-range beta particle emitter, tritium ((3)H). METHODS: Subconfluent monolayers of rat liver epithelial cells (WB-F344) were incubated in the presence of (methyl-(3)H)thymidine ((3)HTdR) at concentrations ranging between 5.2 kBq/ml and 57.8 kBq/ml for 18 h. Radiolabeled cells, containing between 0.7 x 10(-3) Bq/cell and 8.8 x 10(-3) Bq/cell were mixed with unlabeled (i.e., bystander) cells in a ratio of 1:1 and cultured together for 24 h followed by an flow cytometry (FCM) study of their proliferation. In order to discriminate the two populations of co-cultured cells, one cell population (unlabeled bystander cells) was stained with carboxyfluorescein diacetate, succinimidyl ester (CFDA SE), which metabolizes intracellularly. The absorbed doses received by the radiolabeled cells that contained 0.7 x 10(-3), 2.5 x 10(-3), and 8.8 x 10(-3) Bq/cell were 0.14, 0.49, and 1.7 Gy, respectively. RESULTS: Cells that were not treated with tritiated thymidine (unlabeled cells), in the presence of radiolabeled cells that received absorbed doses from 0.14-1.7 Gy, showed enhanced cell growth by approximately 9 to 10%. CONCLUSIONS: Cells labeled with (3)HTdR can induce increased proliferation in neighboring unlabeled bystander cells. FCM provides an excellent basis for characterization of proliferative bystander effects in co-culture systems.

Animals↗
PubMed1988

Dosimetry for radiolabelled antibodies--macro or micro?

Three approaches to calculating radiation absorbed doses and answering fundamental questions in radiolabelled antibody therapy are outlined. Conventional macroscopic dosimetry is probably not appropriate for calculations on the small scale of normal tissue and tumour volumes that are of interest in therapy. A better though even more traditional approach is to use the results from beta particle dosimetry. These may be shown to apply down to quite small populations of cells. An approach using the results found in microdosimetric work is probably too far from practical application to be useful at present.

Antibodies, Monoclonal↗
PubMed2001

Miniaturization of a hepatitis C virus RNA polymerase assay using a -102 degrees C cooled CCD camera-based imaging system.

Innovations in detection technologies have allowed us to develop a novel assay in 1536-well plate format and assess the advantages of screen miniaturization compared with conventional high-throughput compound screening in 96- or 384-well plates. An HCV RNA polymerase assay has been miniaturized in 1536-well plates by using a new detection technology known as LEADseeker homogeneous imaging system. It uses a -102 degrees C cooled charge-coupled device (CCD) camera and newly designed scintillation proximity microparticles. The miniaturized assay used europium-doped streptavidin-coated yttrium oxide (YO(x)) or polystyrene (PS) microspheres to capture biotin-labeled [(3)H]RNA product transcripts. Beads in proximity to the radioisotope convert the emitted beta(-) particles into photons having wavelengths in the red region of the visible spectrum, optimal for detection by the CCD camera. Because the camera collects light from all wells of the plate simultaneously, 1536-well plates are imaged as rapidly as 384-well plates, on the order of 10 min per plate. The assay has a signal to background of approximately 20-fold, satisfactory for high-throughput robotics screening. The enzyme kinetics and potency of a known inhibitor were similar to those obtained from the conventional assay using scintillation proximity assay (SPA) beads and a scintillation plate counter. Furthermore, the newly developed microbeads (emitting at 610 to 620 nm) are less prone to quenching effects caused by yellow-colored compounds, than conventional SPA beads or scintillation fluid (emitting at 400 to 480 nm region). Thus, the LEADseeker imaging system is a useful new tool for miniaturization of assays for high-throughput screening.

Cold Temperature↗
PubMed1994

Glucose diffusion coefficients determined from concentration profiles in EMT6 tumor spheroids incubated in radioactively labeled L-glucose.

A method for performing and evaluating autoradiography of diffusible 14C labeled substances in multicellular tumor spheroids is presented that allows one to obtain a diffusion coefficient of the substance investigated from each individual spheroid. Application of the method with 14C labeled L-glucose resulted in a glucose diffusion coefficient of 5 x 10(-6) cm2/s. It also revealed problems of the method at very short incubation times of about 10 s or less. These problems are most likely caused by the large penetration depth of beta particles irradiated by 14C labels (as compared to 3H labels) which tends to transform steep 14C concentration gradients into much more shallow optical density gradients during exposure. This transformation can be corrected for by deconvolution of the recorded optical density distributions. Basic data and mathematical tools necessary for the process of deconvolution are presently being developed. It is planned to use this method for determining diffusion coefficients of other substances of interest. One such group of substances are the metabolic waste products, most importantly lactate. Another group consists of larger molecules, e.g. peptides and comprises the various growth factors important in tumor biology. Since for members of this latter group little is known about their velocity of penetration into tissue, model calculations may be applied to predict a range of incubation times suitable for determining diffusion coefficients. Moreover, the algorithms for data analysis will have to be modified to allow for receptor binding of the substance under study.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

The presence of two populations of sensory-type cells in the pineal organ of the five-bearded rockling, Ciliata mustela L. (Teleostei).

The pineal organ of the five-bearded rockling, Ciliata mustela L., was examined by means of electron microscopy. Two categories of sensory cells are described: 1) Sensory cells 1 (or photoreceptor cells sensu stricto) showing the characteristic ultrastructure of photoreceptor cells with a well-developed receptor pole (outer segment) and a transmitter pole (ribbon-type synapse in the basal pedicle contacting dendritic processes), and a segmental organization of organelles. 2) Sensory cells 2 (or photoneuroendocrine cells) displaying no particular segmentation. The ultrastructure of the receptor pole (outer segment) is variable in shape (with either long or short disks) and in the number of disks; some outer segments are simple cilia of the 9 + 0 type. This second cell category is rich in smooth endoplasmic reticulum, beta-particles of glycogen, dense inclusions of variable size and content, and dense-core vesicles 130 nm in diameter. These cells have an extended contact area with the perivascular space. The functional significance of both cell categories is discussed in terms of the known physiological responses of the pineal organ. A possible confusion in identification of interstitial cells and neuroendocrine cells in some teleost species is discussed.

Animals↗
PubMed1978

Effect of castration and testosterone administration on the neuromuscular junction in the levator ani muscle of the rat.

The ultrastructure of the neuromuscular junction (n.m.j.) of the androgen-sensitive levator ani muscle was studied in normal adult male rats, in 8-month-old rats castrated at the age of one month and in castrated rats treated with testosterone propionate (TP). Castration does not result in significant changes of the n.m.j. The density of synaptic vesicles and the postsynaptic junctional folds remain practically normal inspite of marked atrophy of the muscle. TP administration for 7 days results in marked changes in pre- and postsynaptic structures. There is slow progressive depletion of synaptic vesicles, appearance of cisternae and coated vesicles in axon terminals, and coalescence of coated vesicles with the plasma membrane. Coated vesicles are also found inside Schwann cells and among junctional folds. Dense core vesicles appear both in the axon terminals and in the postsynaptic area. Collateral sprouting of terminal axons with the formation of new immature junctions is observed. After 35 days of TP administration depletion of synaptic vesicles continues. Glycogen beta-particles, mostly freely dispersed, occasionally seen in axon terminals 7 days after TP administration, subsequently increase in number. In the endplate zone of the muscle fibre increased protein synthesis is indicated by a rapid increase in ribosomes and irregularly located myofilaments and myofibrils. The appearance of n.m.j. after testosterone administration resembles that described after nerve stimulation; the degree of change is however less pronounced.

Animals↗
PubMed1984

Measurement of intracellular 42K diffusion in frog ventricular strips.

The longitudinal distribution of 42K was measured in strips of frog ventricular muscle placed in a partitioned perfusion chamber. A radiation detector placed directly under the chamber was moved from point to point to scan the longitudinal distribution of 42K. The detector was focussed on a 0.6 mm segment of the strip by means of two slits and two Geiger tubes. A beta-particle from the strip was counted only if it passed through both Geiger tubes. This arrangement improved the spatial resolution and decreased the background and the sensitivity to Compton electrons. The intracellular diffusion constant measured with this system is 3.7 X 10(-6) cm2/s.

Animals↗
PubMed1987

Glycogen accumulation in synaptic boutons in Clarke's nucleus neuropil after sciatic nerve crush at birth. An electron microscopic study.

Glycogen accumulation in the Clarke's nucleus neuropil of young adult rats whose sciatic nerves were crushed in the first postnatal day was investigated with the electron microscope. Glycogen was observed in synaptic boutons and in small myelinated axons. In some terminals, glycogen accumulated in membrane-bound structures resembling mitochondria and formed large multigranular bodies which were entirely separated from the axoplasm. The multigranular body reached the size of 1.3 micron. Glycogen was present as single beta particles of about 25-40 nm in diameter and in aggregations of large alpha clusters. The astrocytic glycogen distribution was almost similar to that of the control specimens. Glycogen was not observed in other glial cells. It is probable that glycogen accumulation in synaptic terminals of partially deafferentiated Clarke's nucleus may result from impaired glycolysis due to deficient resupply of the distal axon with glycolytic enzymes caused by a defect in axoplasmic transport from the hypoplastic sensory neuronal perikarya.

Animals↗
PubMed1976

Polarized bremsstrahlung not the source of optical activity.

An evaluation is made of the previously proposed scheme (polarized beta-particles leads to circularly polarized bremsstrahlung leads to optically active molecules) by which dissymmetry at the elementary particle level may be transmitted to the molecular level. The calculations suggest that much too small a fraction of the total energy of the electron appears as light, capable of causing photochemical resolution, to explain results obtained in the laboratory on the preferential radiation-induced decomposition one enantiomer of chiral amino acids.

Amino Acids↗
PubMed1979

On the physical origin of biological handedness.

In the racemic conglomerate crystallization of over 1,000 samples of D,L-sodium-ammonium tartrate the effect of 32P beta irradiation on the weight, optical activity, and crystallite size was measured. Both weight and optical activity showed a statistical dependence on the intensity of beta irradiation. The crystallite size is also affected by the presence of 32P. Asymmetric crystals are suggested to have been potential mediators between asymmetric parity violating forces and molecular asymmetry so that stereo-selective prebiotic chemical reactions involving crystals need not be considered 'chance' processes. No measurable difference in the energy content of optical isomers was found. An upper limit for the direct contribution of weak interactions to electromagnetic ones has been calculated. The mechanism of stereoselective crystal seeding by beta particles is discussed.

Crystallization↗