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S J Adelstein

Publications and source records attributed to S J Adelstein.

At least 73 records · Page 4Linked to original sources
PubMed1989

Radiotoxicity of an 125I-labeled DNA intercalator in mammalian cells.

To explore the effect of the Auger electron emitter 125I attached to a DNA intercalator, we have synthesized 125I- and 127I-labeled 3-acetamido-5-iodoproflavine (AIP) and have examined the uptake, intracellular distribution, and radiotoxicity of A125IP in Chinese hamster V79 cells. After incubation with AIP, the nuclei of V79 cells become fluorescent. Uptake of A125IP is directly proportional to its extracellular radioactive concentration and reaches a plateau at about 10 h. Of the cell-associated radioactivity, 60% is retained by the cells after extensive washing. When the survival of V79 cells is plotted as a function of radioactive cell content, the curve has no shoulder with a mean lethal dose (DN) of about 1.3 Gy to the cell nucleus. Because the DN of these cells when irradiated with 250 kVp X rays is 5.8 Gy, the relative biological effectiveness (RBE) of A125IP is about 4.5. The dependence of the RBE values on the localization of the Auger emitter is discussed on the basis of our extended studies on the same cell line.

Animals↗
PubMed1989

Radiotoxicity of 5-[123I]iodo-2'-deoxyuridine in V79 cells: a comparison with 5-[125I]iodo-2'-deoxyuridine.

The toxic effects of the short-lived (T 1/2 = 13.2 h) Auger-electron-emitting isotope 123I, incorporated in the form of 123IUdR into the DNA of V79 cells in vitro, have been investigated and compared to those of 125IUdR. For the concentrations tested, the rate of incorporation of 123IUdR at any time is proportional to the concentration of extracellular radioactivity. The curve for survival of clonogenic cells decreases exponentially and exhibits no shoulder at low doses. The mean lethal dose (D37) to the nucleus is 79 +/- 9 cGy and is about the same as that obtained previously with 125IUdR. However, the total number of decays needed to produce this D37 with 123IUdR is about twice that required with 125IUdR, approximately equal to the ratio of the energy deposited in microscopic volumes by 125I and 123I, respectively. This correlation suggests that nuclear recoil, electronic excitation, and chemical transmutation are probably of minor importance to the observed biological toxicity with either isotope. The results also indicate that there are no saturation effects in the decay of 125IUdR in the DNA of V79 cells (i.e., all of the emitted energy is biologically effective) and that each of the two steps involved in the 125I decay is equally effective in causing biological damage.

Animals↗
PubMed1989

Limitations of conventional internal dosimetry at the cellular level.

A theoretic examination of the validity at the cellular level of assumptions used in classic internal dosimetry has been undertaken. An alternate dosimetric model accounting for the consequences of selective uptake of a radiolabeled compound by specific cells in a multicellular cluster of hexagonal geometry has been developed. At the cellular level, derived dose estimates for electrons have been compared to dose estimates obtained employing the assumptions of conventional internal dosimetry. The study has been performed for all electron energies and then applied specifically to electrons emitted by 99mTc, 201Tl, 111In, and 123I. The dosimetric consequences of altering (a) the intracellular-to-extracellular radionuclide concentration, (b) the labeled cell density, and (c) the cell size have been examined for the labeled and nonlabeled cells in a cell cluster, and the conditions in which conventional dosimetry underestimates or overestimates the dose to individual cells have been indicated. It is shown that when selective intracellular uptake of a radiolabeled compound occurs in specific cells within a cell cluster, conventional dosimetry underestimates the radiation dose delivered to the labeled cells by twofold to more than 25-fold if the emitted electrons have ranges of a few micrometers or less, i.e., energies smaller than approximately 10 keV. Under the same conditions, conventional dosimetry overestimates slightly (20% to 50%) the electron radiation dose to the nonlabeled cells of the cell cluster. It is shown that inclusion of photons in the calculation of the total dose to individual cells does not alter significantly the conclusions of the present investigation.

Electrons↗
PubMed1988

Radioimmunotherapy with alpha-particle-emitting immunoconjugates.

Alpha particles are energetic short-range ions whose higher linear energy transfer produces extreme cytotoxicity. An alpha-particle-emitting radioimmunoconjugate consisting of a bismuth-212-labeled monoclonal immunoglobulin M specific for the murine T cell/neuroectodermal surface antigen Thy 1.2 was prepared. Analysis in vitro showed that the radioimmunoconjugate was selectively cytotoxic to a Thy 1.2+ EL-4 murine tumor cell line. Approximately three bismuth-212-labeled immunoconjugates per target cell reduced the uptake of [3H]thymidine by the EL-4 target cells to background levels. Mice inoculated intraperitoneally with EL-4 cells were cured of their ascites after intraperitoneal injection of 150 microcuries of the antigen-specific radioimmunoconjugate, suggesting a possible role for such conjugates in intracavitary cancer therapy.

Alpha Particles↗
PubMed1987

Uncertainty and relative risks of radiation exposure.

Exposure to ionizing radiation in a nonmilitary emergency is likely to alarm those persons exposed and their families. Not only is the outcome uncertain, but the risks are difficult to convey. This communication discusses uncertainties in short-term outcome and long-term effects, as well as means of conveying the magnitude of risks to patients and their families. It emphasizes that the perception of radiation hazards is contextual. It offers three ways of presenting the prognostic long-term risks of accidental radiation exposure by comparing them with the incidence of cancer and genetic abnormalities in unexposed persons, the hazards of everyday living, and the level of natural and medical exposures to ionizing radiation.

Humans↗
PubMed1987

HPLC analysis of the dissociation and recombination of rabbit immunoglobulin G.

Rabbit immunoglobulin G (RIgG) was reduced with dithioerythritol and analyzed by high performance liquid chromatography. A quantitative method for determining the percentage of reduced half-molecules in the mixture was developed. An acetic acid concentration-dependent rate of dissociation of reduced half-molecules was observed. The specific optical absorptivity was determined for whole molecules and half-molecules and found to be significantly greater for the half-molecules. Purified half-molecules were reconstituted into RIgG with a yield greater than 90% following a 16 h incubation at pH 8.0 and room temperature.

Acetates↗
PubMed1987

Formation of strand breaks in the DNA of gamma-irradiated chromatin.

Strand breaks have been determined by sedimentation on sucrose gradients in the DNA of chromatin irradiated after isolation from Chinese hamster lung fibroblasts. The yields of double-strand and single-strand breaks are similar to those found in the DNA of irradiated mammalian cells. Irradiation of isolated chromatin in the presence of the radical scavenger tertiary butanol indicates that at least 65% of single-strand breaks and 56% of double-strand breaks can be attributed to the action of hydroxyl radicals. The results indicate the influence of chromosomal proteins in modifying radiation damage to DNA and suggest that the mechanisms for the induction of strand breaks in the DNA of isolated chromatin may be comparable to those operating in the intact cell.

Animals↗
PubMed1987

Radiobiologic implications of the microscopic distribution of energy from radionuclides.

A significant increase in our understanding of the dosimetry and therapeutic potential of various types of radioactive decay has augmented the possibility of utilizing specific radiolabeled carriers in tumor therapy. At least three types of radioactive decay lend themselves to this approach. Most fastidious in their distribution requirements are the Auger electron emitters whose radiotoxicity can only be realized with their intranuclear localization. Alpha emitters irradiate regions of several cell diameters. Beta emitters are less stringent as far as proximity to the total tumor mass, but doses to normal tissues can be high. The advantages and the limitations of each type of decay are presented.

Alpha Particles↗
PubMed1987

Synthesis and biological studies of iodinated (127/125I) derivatives of rhodamine 123.

Rhodamine 123, a mitochondrial stain that preferentially accumulates in certain cancer cells, has been reduced and iodinated by using NaI in the presence of N-chlorosuccinimide. The various mono-, di-, and triiodo derivatives have been isolated and characterized. These nonfluorescent compounds are taken up by mammalian cells, become fluorescent within the cytoplasm (presumably following oxidation), and show the same pattern of localization as the parent compound. Iodination with no-carrier-added Na125I yields the same mixture of compounds. All 125I derivatives accumulate preferentially in PC3 adenocarcinoma cells compared with V79 lung fibroblasts, with the differential being greatest for the monoiodo compound, followed by the di- and triiodo derivatives.

Adenocarcinoma↗
PubMed1987

Radiation damage to histone H2A by the primary aqueous radicals.

Histone H2A has been examined for radiation-induced changes in structure and in amino acid composition. The effects of the individual radical intermediates--the hydroxyl radical, solvated electron, and superoxide radical--have been determined by irradiating in dilute aqueous solution under controlled environmental conditions. Amino acid analysis of irradiated histone H2A shows a selective attack on a few residues; only the aromatic residues, phenylalanine and tyrosine, and the heterocyclic residue, histidine, are significantly decreased. A significant increase in aspartic acid is also observed. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis shows that the hydroxyl radical is the effective radical for promoting changes in protein structure.

Amino Acids↗
PubMed1987

Radiotoxicity of 125I in mammalian cells.

The radiotoxicity of 125I in Chinese hamster V79 lung fibroblasts has been studied following extracellular (Na125I), cytoplasmic [125I]iododihydrorhodamine (125I-DR), and nuclear (125IUdR) localization of the radionuclide. Exposure of the cells for 18 h to Na125I (less than or equal to 7.4 MBq/ml) had no effect on survival. A similar exposure to 125I-DR produced a survival curve with a distinct shoulder and with a mean lethal dose (D37) of 4.62 Gy to the nucleus. While this value compares well with the 5.80 Gy X-ray D37 dose, it is in contrast to the survival curve obtained with DNA-bound 125IUdR which is of the high LET type and has a D37 of 0.80 Gy to the nucleus. Furthermore, when the uptake of 125I into DNA is reduced by the addition of nonradioactive IUdR or TdR to the medium and the survival fraction is determined as a function of 125I contained in the DNA, a corresponding increase in survival is observed. This work demonstrates the relative inefficiency of the Auger electron emitter 125I when located in the cytoplasm or outside the cell. It indicates that a high dose deposited within the cytoplasm contributes minimally to radiation-induced cell death and that radiotoxicity depends not upon the specific activity of IUdR but upon the absolute amount of 125I that is associated with nuclear DNA.

Animals↗
PubMed1987

Kinetics of uptake, retention, and radiotoxicity of 125IUdR in mammalian cells: implications of localized energy deposition by Auger processes.

The kinetics of uptake, retention, and radiotoxicity of 125IUdR have been studied in proliferating mammalian cells in culture. The radioactivity incorporated into the DNA is directly proportional to the duration of incubation and to the extracellular concentration of 125I. The rate of proliferation of cells is related to the intracellular radioactive concentration and is markedly reduced at medium concentrations greater than or equal to 0.1 mu Ci/ml. At 37% survival the high LET type cell survival curve is characterized by an uptake of 0.035 pCi/cell, and the cumulated mean lethal dose to the cell nucleus is about 80 rad compared to 580 rad of X-ray dose for this cell line. The strong cytocidal effects of the decay of 125I correlate with localized irradiation of the DNA by the low energy Auger electrons.

Animals↗
PubMed1986

Organoastatine chemistry. Astatination via electrophilic destannylation.

Substantial interest is currently focused on the alpha-emitting radiohalogen 211At, principally because of its potential use in the radiation therapy of cancer. Knowledge of organoastatine chemistry is incomplete and existing methods for its incorporation restrict the range of compounds which may be labeled. Aryl and vinyl Sn(IV) compounds are notably susceptible to substitution of tin by a variety of electrophiles. We have investigated the reaction of aryltrialkylstannanes with astatine and report here the first examples of astatodestannylation. Formation of aryl astatides proceeds rapidly, cleanly and under mild conditions. The data further elucidate aspects of astatine reactivity and suggest a general route to synthesize astatinated compounds.

Astatine↗
PubMed1986

Radiation synovectomy with 165Dy-FHMA: lymph node uptake and radiation dosimetry calculations.

The lymph node uptake of 165Dy was measured in 25 patients treated by radiation synovectomy via intra-articular injection of 165Dy-ferric hydroxide macroaggregates (FHMA). An average of 0.12% of the injected dose was found in the inguinal lymph nodes 19h post injection. This results in a lymph node of 16.6 rad (166 mGy), a dose significantly less than that reported following radiation synovectomy with other radiocolloids. Dosimetry calculations for the intra-articular injection of 165Dy-FHMA are provided in the appendix.

Arthritis, Rheumatoid↗
PubMed1986

The in vitro radiobiology of astatine-211 decay.

Chinese hamster V79 cells in culture were exposed to astatine-211, an alpha-particle-emitting radiohalogen. The dose-log survival response was linear with no detectable shoulder. Cells in monolayers had a D0 of 1.0 microCi/ml. Suspended cells had a D0 of 0.60 microCi/ml with a cellular uptake of 2.5 fCi/cell; this is equal to approximately 1.5 alpha-particle traversals per cell nucleus. The frequencies of chromosome and chromatid breaks were linear with dose, but the number declined rapidly with time. These data are discussed in relation to published alpha-particle beam studies and the potential use of 211At in radionuclide therapy.

Alpha Particles↗
PubMed1985

Chemotoxicity of indium-111 oxine in mammalian cells.

We have studied the uptake and toxicity of [111In]oxine in Chinese hamster V79 lung fibroblasts. The incorporation of the radionuclide into these cells reached a plateau within 2 hr. Uptake was proportional to the extracellular radioactive concentration. Both radioactive and "decayed" [111In]oxine exhibited similar toxicities, indicating that the observed toxicity was chemical in nature. These results are discussed in terms of the present status of this radiolabeling agent.

Animals↗
PubMed1985

Intracellular distribution and radiotoxicity of chromium-51 in mammalian cells: Auger-electron dosimetry.

The kinetics of uptake and of radiotoxicity of chromium-51, an Auger-electron emitter, have been studied in V79 lung fibroblasts of the Chinese hamster. Intracellular radioactivity was directly proportional to the incubation period and to the extracellular concentration of the Cr-51. About 14% of the cellular activity was associated with the nucleus, whereas approximately 2% was guanidine-precipitable and therefore bound to DNA. The growth rate of V79 cells was slowed following intracellular incorporation of Cr-51. The cell-survival curve, in terms of colony-forming ability, was of the low-LET type, with a D37 of 6.2 pCi/cell. Theoretical dosimetric estimates indicate that, under the given experimental conditions, the mean lethal dose to the cell nucleus was 870 rad. Although this value is somewhat larger than the x-ray D37 dose of 580 rad for this cell line, it is more realistic than the gross underestimate obtained by classical MIRD calculations (2-3 rad/cell).

Animals↗