Search PubMed⌕ Search

Biomedical subjects

S J Adelstein

Publications and source records attributed to S J Adelstein.

At least 19 recordsLinked to original sources
PubMed1992

DNA damage produced in V79 cells by DNA-incorporated iodine-123: a comparison with iodine-125.

The neutral elution technique (pH 9.6) has been used to compare the damage produced in the DNA of V79 cells following the decay of the Auger-electron emitters 123I and 125I incorporated into DNA in the form of 5-[123I/125I]iodo-2'-deoxyuridine (123IdU, 125IdU) or after 60Co gamma irradiation. Elution profiles of retained radioactivity versus eluted volume were generally found to be nonlinear and partially dependent on the cell treatment prior to elution. Plots of a suitable function of radioactivity retention on the filters versus total decays for 123I or 125I and dose (Gy) for gamma radiation were linear. Assuming that each 125I decay produces one double-strand break (DSB), the 60Co efficiency in DSB production was found to be 53.4 DSBs/Gy/cell (or 17.8 DSBs/Gy/10(12) Da), in agreement with values reported previously. The decay of 123I led to 0.74 DSB/decay/cell if decays occurring only during nonrepair conditions were counted. This DSB production efficiency is in agreement with Monte Carlo semiempirical models of the action of radiation on DNA.

Animals↗
PubMed1991

5-[123I]iodo-2'-deoxyuridine in the radiotherapy of an early ascites tumor model.

The extreme biological toxicity of Auger emitters is caused by the decay-associated, highly localized deposition of energy. The antineoplastic capability of an Auger-electron emitter, iodine-123, incorporated into the thymidine analog, 5-iodo-2'-deoxyuridine (IUdR) was evaluated in an intraperitoneal (i.p.) murine ovarian tumor (MOT) in female C3HeB/FeJ mice. Total doses of 0.37 to 8.88 MBq (10-240 microCi) 123IUdR were administered i.p. in five equally divided fractions at 24, 28, 32, 36, and 40 hr after the i.p. inoculation of 0.5 to 1.6 x 10(6) tumor cells per mouse. Control tumor-bearing animals were injected with identical volumes of saline at 4-hr intervals. Biodistribution studies demonstrated a distinct and localized uptake of 123IUdR in the MOT cells (1% of the injected dose was associated with MOT cells 24 hr after the last injection), whereas in animals without tumor there was no radioactivity associated with the peritoneal cells. Analogous results were obtained from scintigraphic images where the focal area of abdominal activity persisted only in MOT-bearing mice while it cleared from the abdomen of the controls. The 50% survival (median survival) of the control group was 19 days for an inoculum of 1.6 x 10(6) MOT cells per animal, whereas the median survival of MOT-bearing animals treated with 123IUdR increased by 11 days for the highest administered dose (8.88 MBq, 240 microCi) and resulted in a 20% absolute survival at 7 weeks. Statistically significant absolute survival prolongation was found with all of the total administered doses. The prolongation of both median and absolute survival time of the tumor-bearing animals treated with 123IUdR conclusively indicates the substantial antineoplastic activity of the Auger-electron emitter iodine-123.

Animals↗
PubMed1991

Potential for tumor therapy with iodine-125 labeled immunoglobulins.

Because of the high intranuclear toxicity of Auger-electron emitters, the use of radioiodinated (123I, 125I) 5-iodo-2'-deoxyuridine (IUdR)-antibody conjugates for cancer therapy has been examined. The results have demonstrated that all the conditions necessary for labeling DNA in vivo are present: uptake of the radiolabeled immunoglobulin by target cells, its subsequent internalization, the degradation of the IUdR-protein conjugate by lysosomal enzymes, and the incorporation of the radionucleoside into DNA.

Humans↗
PubMed1991

Antigen-binding site protection during radiolabeling leads to a higher immunoreactive fraction.

It is generally accepted that the immunointegrity of an antibody (Ab) depends on the preservation of its antigen-binding sites. Our goal was to radiolabel an antibody at several iodine:antibody molar ratios under conditions protecting its combining site and to compare its immunoreactive fraction (IRF) and electrophoretic mobility with those of the same antibody radiolabeled without protection. The data indicate that an antibody radiolabeled while its antigen-binding site is occupied by its antigen had the same IRF, regardless of the number of iodine atoms per antibody molecule. On the other hand, even at an I:Ab ratio of 1:1, the IRF of the same antibody radiolabeled without protection was lower than that of a protected one and decreased with increasing I:Ab ratios. In addition, the iodination of these Ab changes their electrophoretic mobility; however, when the Ab is labeled in the protected state, the degree of change is less. The binding of an antibody to its antigen prior to radiolabeling, therefore, enhances its immuno-integrity and prevents major conformational changes as reflected by electrophoresis.

Animals↗
PubMed1990

Specific uptake of the auger electron-emitting thymidine analogue 5-[123I/125I]iodo-2'-deoxyuridine in rat brain tumors: diagnostic and therapeutic implications in humans.

Glial neoplasms of the human central nervous system are malignancies that have defied treatment. Part of the problem lies in the limitations of current diagnostic techniques which are unable to identify small collections of neoplastic glia within normal parenchyma and in the difficulty of sterilizing these tumors because of limited selectivity of the cytotoxic agents available. The thymidine analogue 5-iodo-2'-deoxyuridine (IdUrd) radiolabeled with 123I and 125I was injected directly into an intracerebral rat 9L gliosarcoma and found to be a sensitive and specific agent for the detection of this neoplasm in rats. External gamma camera imaging (123I) visualized tumors as small as 0.5 mm in diameter. Autoradiography (125I) indicated that IdUrd was incorporated into the DNA of neoplastic glia only. Since 123I emits gamma-photons suitable for scintigraphy, [123I]IdUrd holds promise for the diagnosis of brain tumors in humans as well. Furthermore, since 123I and 125I are Auger electron emitters that have demonstrated antineoplastic effects, direct administration of [123I]IdUrd or [125I]IdUrd into tumors may also have potential for the treatment of central nervous system malignancies.

Animals↗
PubMed1990

Cellular radiation dosimetry and its implications for estimation of radiation risks. Illustrative results with technetium 99m-labeled microspheres and macroaggregates.

Radiation absorbed doses at the cellular level were calculated for routine, human lung perfusion examinations after the intravenous injection of technetium 99m-labeled microspheres or macroaggregated albumin. In such studies, more than 90% of these particles are trapped in the precapillary arterioles of the lung, resulting in an extremely inhomogeneous distribution of radionuclide. We used a computer program that accounted for the inhomogeneity of radiopharmaceutical distribution and calculated the dose to individual lung cells. Absorbed doses to individual lung cells were found to vary by a factor of about 30,000. We believe that such findings call for a reevaluation of the justification for dosimetry at the organ level and an examination of the implications of absorbed doses calculated at the cellular level for the estimation of radiation risks.

Dose-Response Relationship, Radiation↗
PubMed1990

Auger electron emitters: insights gained from in vitro experiments.

This paper outlines the evolution of the current rationale for research into the biological effects of tissue-incorporated Auger electron emitters. The first section is a brief review of the research conducted by several groups in the last fifteen years. The second section describes the in vitro model used in our studies, dosimetric calculations, experimental techniques and recent findings. The third section focuses on the use of Auger electron emitters as in vitro microprobes for the investigation of the radiosensitivity of distinct subcellular components. Examination of the biological effects of the Auger electron emitter 125I located in different cellular compartments of a single cell line (V 79 hamster lung fibroblast) verifies that DNA is the critical cell structure for radiation damage and that the sensitive sites are of nanometer dimensions. The data from incorporation of several Auger electron emitters at the same location within DNA suggest that there are no saturation effects from the decay of these isotopes (i.e. all the emitted energy is biologically effective) and provide some insight into which of the numerous physical mechanisms accompanying the Auger decay are most important in causing cell damage. Finally the implications of Auger electron emission for radiotherapy and radiation protection in diagnostic nuclear medicine are detailed and further research possibilities are suggested.

Cell Survival↗
PubMed1990

Synthesis and biological activity of the intercalating agent 3-acetamido-5-[123/125I]iodo-6-aminoacridine.

3-Acetamido-5-iodo-6-aminoacridine (3), a derivative of the known intercalating agent proflavine (3,6-diaminoacridine) (1) was synthesized, and no-carrier-added 123I and 125I labeled compounds prepared. Compound 3 was taken up by live cells and localized in the nucleus. The intracellular concentration of [125I]3 was 7-fold greater in human prostate carcinoma (PC-3) cells than in normal Chinese hamster lung fibroblast (V-79) cells.

Acridines↗
PubMed1990

Mutation induction by 125iodoacetylproflavine, a DNA-intercalating agent, in human cells.

Survival and the induction of mutations at the hprt and tk loci were measured in TK6 human lymphoblastoid cells following treatment with the DNA-intercalating agent 125iodoacetylproflavine (125IAP). 125IAP was readily taken up into the cells, was localized to the nucleus, and was released rapidly following resuspension of the cells in fresh medium. Treatment with 125IAP for 24 h yielded a D0 of 110 decays/cell and an induced mutant fraction of 0.13 x 10(-6) per decay at the hprt locus and 0.4 x 10(-6) per decay at the tk locus. Molecular analyses of 125IAP-induced hprt mutants by Southern blot revealed a high proportion of large-scale changes at this locus. When these results are compared with those observed with 125IdUrd, 125IAP shows a reduced effectiveness per decay, related perhaps to the non-covalent nature of intercalator binding, resulting in reduced energy deposition in the DNA.

Acridines↗
PubMed1990

5-iodo-2'-deoxyuridine-protein conjugates: synthesis and enzymatic degradation.

Several halogenated analogs of thymidine and cytidine possess antineoplastic and antiviral activity. They are also powerful sensitizers of bacterial and mammalian cells to lethal effects of x-irradiation. An important factor limiting the effectiveness of these agents in therapy is their extremely short half-life in circulation due to rapid hepatic dehalogenation. An approach to this problem is to deliver the drug directly to its target using monoclonal antibodies. This study evaluates the lysosomotropic delivery systems of halogenated pyrimidines using 5-iodo-2'-deoxyuridine [IUdR] as a model. IUdR, derivatized and activated at either the 3'- or the 5'-position forms covalent adducts with the epsilon-amino groups of the lysine residues in proteins (bovine serum albumin [BSA], and immunoglobulins [IgG]). Two methods suitable for conjugation of IUdR to proteins involving either the formation of acyl-imidazoles in the reaction of IUdR succinates with N,N'-carbonyldiimidazole or the preparation of N-succinimidyl esters of IUdR succinates were established. Both derivatives express comparable reactivity toward proteins. The degree of IUdR incorporation is easily controlled by the ratio of reagents. The succinate "arm" linking IUdR to protein is susceptible to lysosomal hydrolysis in vitro releasing intact IUdR. The half-life of the IUdR-IgG conjugate in the presence of the lysosomal enzymes was shown to be approximately twice that of the IUdR-BSA conjugate.

Antineoplastic Agents↗
PubMed1990

Inhomogeneous deposition of radiopharmaceuticals at the cellular level: experimental evidence and dosimetric implications.

We have undertaken an experimental examination of the conventional internal dosimetry assumptions of homogeneity of radionuclide deposition in tissues. The distribution of radiolabeled Microlite has been quantitated in mouse liver at the millimeter (multicellular) and the micrometer (cellular) levels. Measurements of radioactivity in 1-mm3 tissue samples indicate homogeneous radionuclide distribution; those derived from autoradiographs of 0.5-micron tissue sections show that, relative to other cells, the colloid was concentrated 200- to 1000-fold in liver macrophages. The dosimetric implications of such inhomogeneous radionuclide distribution in human liver, where similar radionuclide distribution is expected, are discussed on the basis of a recently developed model for calculating the dose at the cellular level, and the estimates are compared to conventional internal dosimetry predictions. It is demonstrated that during routine diagnostic examinations with 99mTc-Microlite, conventional dosimetry underestimates the dose to labeled human liver cells by factors of 8-30.

Animals↗
PubMed1989

Absence of preferential uptake of [125I]iododihydrorhodamine 123 by four human tumor xenografts.

The biodistribution of [125I]iododihydrorhodamine 123 has been studied over a 96-h period in four human tumor xenograft models: HT-29 colon adenocarcinoma, PC-3 prostate carcinoma, HT-1080 fibrosarcoma, and PaCa-2 pancreatic carcinoma. Elimination of radioactivity in the tumor-bearing nude mice was rapid during the first 24 h and slow thereafter. The lack of uptake in the thyroid indicated there was little, if any, deiodination of the molecule. Activity was found mainly in the liver and spleen. Accumulation of radioactivity was low in all four tumors examined. At 4 h postinjection, as well as at 24 and 48 h, however, the total radioactive content in each of the four tumors was directly proportional to the weight of the tumor sample. This correlation was independent of tumor type, route of injection (i.v./i.p.) or dose (1.2-6 microCi/mouse). This was not true for any of the normal tissues, suggesting that this accumulation may be governed by certain intrinsic characteristics of the cancers tested.

Adenocarcinoma↗
PubMed1989

The physician's responsibility toward hopelessly ill patients. A second look.

Physicians have a specific responsibility toward patients who are hopelessly ill, dying, or in the end stages of an incurable disease. In a summary of current practices affecting the care of dying patients, we give particular emphasis to changes that have become commonplace since the early 1980s. Implementation of accepted policies has been deficient in certain areas, including the initiation of timely discussions with patients about dying, the solicitation and execution in advance of their directives for terminal care, the education of medical students and residents, and the formulation of institutional guidelines. The appropriate and, if necessary, aggressive use of pain-relieving substances is recommended, even when such use may result in shortened life. We emphasize the value of a sensitive approach to care--one that is adjusted continually to suit the changing needs of the patient as death approaches. Possible settings for death are reviewed, including the home, the hospital, the intensive care unit, and the nursing home. Finally, we consider the physician's response to the dying patient who is rational and desires suicide or euthanasia.

Ethics, Medical↗
PubMed1989

Monoclonal antibody internalization by tumor cells: an experimental model for potential radioimmunotherapy applications.

The monoclonal IgM 3G5, which reacts with the surface membranes of rat insulinoma cells RINm5F, was purified by HPLC and labeled with 125I using Protag-125; bovine IgG (bIgG) was similarly radiolabeled, and used as a control. 125I-3G5 was incubated with RINm5F cells either at 4 degrees C or at 37 degrees C. 125I-3G5 bound onto RINm5F cells growing in Petri dishes remained approx. constant over 44 h when incubated at 4 degrees C, whereas at 37 degrees C radioactivity was released back in the medium starting at 3 h (plateau at approx. 20 h). At the end of incubation at 37 degrees C, activity in the medium included a high percentage of free 125I (15.69 vs 2.62% for bIgG, and 1% for 3G5 at 4 degrees C). In a cell suspension experiment, cell-bound 125I-3G5 also remained constant over a 24 h incubation at 4 degrees C, whereas at 37 degrees C it decreased to 37.5% of its initial value (64.1% at 4 h). Concomitant microautoradiography showed diffuse radioactive deposits within the RINm5F cells following incubation with 125I-3G5 (but not 125I-bIgG) at 37 degrees C. These results indicate that 3G5-IgM reacts with a surface antigen on the RINm5F cells, but is rapidly internalized by the cells: within the cells, this antibody undergoes some metabolic processing which results in the release of free 125I outside the cells.

Animals↗
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↗