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Biomedical subjects

R M Macklis

Publications and source records attributed to R M Macklis.

At least 55 records · Page 3Linked to original sources
PubMed1993

Morphological, biochemical, and molecular changes in endothelial cells after alpha-particle irradiation.

The response of cultured bovine aortic endothelial (BAE) cells after exposure to alpha-particle radiation from chelated 212Bi has been evaluated. The results suggest that even relatively high doses of alpha-particle radiation from 212Bi (20-72 Gy) cause only minor acute changes in the morphology of BAE cells (light and electron microscopy) under conditions of confluent monolayer growth. Significant morphological changes can be detected in cells that detach from the monolayer, though it is unclear whether these changes represent a genuine response to irradiation or reflect the causes or effects of monolayer detachment with the consequent loss of intercellular biochemical communication. After alpha-particle irradiation (20-40 Gy) angiotensin-converting-enzyme activity was not detectable in the monolayer culture medium but was significantly decreased within the cell monolayer. Neutral-elution-assay data demonstrated that DNA double-strand-break (DSB) damage occurred in these cells and that about 35% of the DSBs were repairable.

Alpha Particles↗
PubMed1993

Internal dosimetry using data derived from autoradiographs.

Cancer therapies based on administered radionuclides require accurate information on tumor dose. One of the major factors influencing the distribution of absorbed-dose characteristics is the uniformity of the radiolabel distribution in tissue. To study the effect of nonuniformities, we used image analysis techniques to measure automatically the coordinates of autoradiographic grains (sources) and cell nuclei in cut sections from three different tumors, following treatment with radiolabeled antibodies. The spatial distribution data of sources and cell nuclei from these tumor sections were assessed and the pattern of energy deposition in the cell nuclei calculated, assuming that each autoradiograph grain corresponded to a source of the alpha emitter astatine-211 (211At) or the beta emitter yttrium-90 (90Y). The distribution of deposited energy obtained for the real grain distributions was compared to the distribution assuming a locally uniform source distribution, i.e., simulating grain count averaging as produced by a microdensitometric method within a 100 x 100 microns 2 frame size (frame averaging), and a uniform distribution across the entire section (section averaging). The results show first that when the grain distribution is uniform, the average dose within the section is an adequate estimate of the dose to the cell nuclei. Second, when the grain distribution is nonuniform, the distribution of doses to the cell nuclei is significantly less when calculations use the measured grain coordinates, or frame averaging, than when section averaging is used. Third, when the sources are located on or in the cells, both frame and section averaging produce underestimates of the dose to the cell nuclei.

Animals↗
PubMed1992

Lymphoid irradiation results in long-term increases in natural killer cells in patients treated for Hodgkin's disease.

Therapeutic lymphoid irradiation has been shown to produce profound long-term alterations in lymphocyte subpopulations and immunologic responsiveness. Dual immunofluorescence flow cytometry and functional cytolytic assays were used to investigate the effects of lymphoid irradiation either alone or in combination with chemotherapy on T-cell and natural killer (NK) cell populations in the blood of patients treated for Hodgkin's disease. Patients treated with mantle and paraaortic lymphoid irradiation show significant increases in the proportion of cells bearing the NK cell phenotypic marker Leu-11 (CD16). These patients also display proportionately increased cytotoxicity against K562 tumor targets in vitro. A sizable number of these NK cells label dimly with Leu-2 (CD8) although they lack the pan-T-cell marker Leu-4 (CD3). The emergence after lymphoid irradiation of this population of Leu-11+2+ NK cells may lead to an apparent decrease in the ratio of helper to suppressor T-cells, although the actual ratio of these T-cell subsets generally is normal. These changes persist for years after the completion of radiation therapy. It was concluded that lymphoid irradiation may produce profound changes in NK cell populations in patients treated for Hodgkin's disease; the clinical significance of these changes is unclear.

Adolescent↗
PubMed1992

Analysis of cytotoxicity of 131I-labelled OC125 F(ab')2 on human epithelial ovarian cancer cell lines.

Monoclonal antibody (mAb) OC125 detects the cell surface-antigen CA125, which is expressed in more than 80% of epithelial ovarian cancers but not in normal adult ovaries. Its high specificity and binding affinity makes OC125 a potential candidate for use in radioimmunotherapy (RIT) in patients with recurrent ovarian cancer. Initial biodistribution studies using radiolabelled specific mAbs have demonstrated significant increase in tumor uptake of dose as compared to radiolabelled irrelevant antibody. We report here an isodose comparison of the cytotoxicity of 131I-labelled OC125 F(ab')2, 131I-labelled nonspecific protein and external beam irradiation using a cesium-137 gamma source. Enhancement of cytotoxity due to the specific binding of the mAb could only be observed when a critical activity of 131I localized at the cell membrane. At a specific activity labelling of less than 4.1 mCi/mg, the antigen specificity of OC125 does not contribute to cell kill. Using a specific activity of 10.2 mCi/mg, the relative biological effectiveness of 131I-labelled OC125 (F(ab')2 was increased by a factor of 5 compared with external-beam X-ray therapy, and the specificity of mAb OC125 was found to enhance the cytotoxicity of the radioimmunoconjugate (RIC) by a factor of 2.7. This low value is in accordance with previously reported theoretical calculations for long range, low-LET isotopes and may be one of the reasons why RIT using 131I has severe limitations. In conclusion, it is necessary to maximize the specific activity of RICs with low-LET isotopes such as iodine-131 in order to maximize the ratio of the dose delivered specifically by membrane-bound mAb versus free-floating nonspecific protein.

Adenocarcinoma↗
PubMed1992

Induction of mutations by bismuth-212 alpha particles at two genetic loci in human B-lymphoblasts.

The human lymphoblast cell line TK6 was exposed to the alpha-particle-emitting radon daughter 212Bi by adding DTPA-chelated 212Bi directly to the cell suspension. Cytotoxicity and mutagenicity at two genetic loci were measured, and the molecular nature of mutant clones was studied by Southern blot analysis. Induced mutant fractions were 2.5 x 10(-5)/Gy at the hprt locus and 3.75 x 10(-5)/Gy at the tk locus. Molecular analysis of HPRT- mutant DNAs showed a high frequency (69%) of clones with partial or full deletions of the hprt gene among radiation-induced mutants compared with spontaneous mutants (31%). Chi-squared analyses of mutational spectra show a significant difference (P < or = 0.005) between spontaneous mutants and alpha-particle-induced mutants. Comparison with published studies of accelerator-produced heavy-ion exposures of TK6 cells indicates that the induction of mutations at the hprt locus, and perhaps a subset of mutations at the tk locus, is a simple linear function of particle fluence regardless of the ion species or its LET.

Alpha Particles↗
PubMed1992

Cellular kinetics, dosimetry, and radiobiology of alpha-particle radioimmunotherapy: induction of apoptosis.

Though clinical results for radioimmunoconjugate therapy of most common epithelial tumors have been disappointing, dramatic responses have been observed repeatedly in the treatment of high- and low-grade malignant lymphomas. This high clinical responsiveness after radioimmunoconjugate therapy sometimes appears to be out of proportion to the calculated radiation dose absorbed by the lymphoma tissue. Here we describe some key aspects of the kinetics, dosimetry, and cellular radiobiology of murine lymphoma cells exposed to 212Bi-radiolabeled alpha-particle-emitting immunoconjugates specific for the differentiation antigen Thy 1.2. Approximately 25 cell-bound alpha-particle-emitting immunoconjugates per target cell were required to reduce clonogenic survival by 90% (the radiobiological D10). Serial kinetic analyses of the antibody and radioisotope components of the immunoconjugates revealed significant levels of dechelation and up to 7.5% cellular internalization of the isotope. Cellular radiation dosimetry performed by Monte Carlo computer simulation of alpha-particle energy deposition patterns based on the observed radiopharmacokinetics showed that the D10 resulted from approximately four alpha-particle traversals through the nucleus, corresponding to an absorbed radiation dose of approximately 0.95 Gy to the cell nucleus. Electron micrographs and DNA gel studies of murine lymphoma cells undergoing radioimmunoconjugate therapy in vivo and in vitro demonstrated bizarre blebbing patterns, condensation of chromosomal material, and internucleosomal DNA fragmentation patterns characteristic of programmed cell death (apoptosis). We conjecture that the efficacy of radioimmunoconjugates against responsive cell types may be the result of passive DNA damage by ionizing radiation and the initiation of apoptosis in response to radioimmunotherapy.

Alpha Particles↗
PubMed1991

Atypical radiation toxicity in patients with classical Kaposi's sarcoma.

The classical (non-AIDS-related) form of Kaposi's sarcoma (KS) typically affects older patients of Eastern European or Mediterranean ethnic background. Although radiotherapy is a standard part of the treatment armamentarium for KS patients, a high incidence of radiotoxicity has been reported in epidemic AIDS-related cases. In order to determine whether this radiotoxicity is observed only in patients with the epidemic form of the disease, we have conducted a retrospective chart review of 30 patients with classical KS treated with radiation for whom follow-up information was available. Seven out of 30 (23%) were found to have unexpectedly high levels of radiotoxicity after tumor doses of 22-42 Gy. This toxicity consisted either of significantly increased edema or chronic skin breakdown and severe radiodermatitis, in some cases requiring multiple surgical corrective procedures. We suggest that the abnormal lymphaticovenous development and chronic lymphokine stimulation associated with KS of both epidemic and classical forms may be responsible in part for the observed radiotoxicity.

Aged↗
PubMed1991

Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies.

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti-CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC-mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC-mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

Adolescent↗
PubMed1991

Wilms' tumor patients with pulmonary metastases.

We have evaluated the clinicopathologic characteristics, survival probabilities, patterns of treatment failure, and late toxicities in a group of 51 Wilms' tumor patients with pulmonary metastases evaluated at our center between 1968 and 1988 and treated intensively with surgery, multiagent chemotherapy, and radiotherapy. Twenty-one patients had pulmonary metastases at diagnosis (Stage IV-p) and 30 had pulmonary relapse after initial treatment for nonmetastatic disease. With a median follow-up time of 83 months, actuarial 5- and 10-year survival probability for the group as a whole is 59%. For the subset of patients with favorable histology Stage IV-p disease, 10-year survival probability is 77%, whereas for the subset with relapsed anaplastic or sarcomatous disease, 10-year survival probability is 22%. The lung was the predominant site of failure even in patients who had received relatively high doses of pulmonary radiotherapy. Late effects seen in patients with over 10 years of follow-up included musculoskeletal and soft tissue growth abnormalities (93% incidence) as well as breast hypoplasia and endocrinologic abnormalities. Second malignant neoplasms of the breast, thyroid, and pancreas were observed at post-treatment intervals of 17, 3.5 and 12 years, respectively.

Child, Preschool↗
PubMed1991

Radiation hormesis.

"Radiation hormesis" is the name given to the putative stimulatory effects of low level ionizing radiation (generally in the range of 1-50 cGy of low-LET radiation). Based on historical and pharmacologic principles reminiscent of some of the major tenets of homeopathy, most of these effects are now generally ascribed to protective feedback systems that, upon exposure to low concentrations of toxins, proceed to stimulate metabolic detoxification and repair networks. The activation of these networks may then result in net beneficial effects on the cell, organism or species. Discussions of possible stimulatory effects of low levels of ionizing radiation have recently become entangled with the separate but related question of whether a threshold dose level exists on the radiotoxicologic dose-response curve. This review summarizes some of the relevant historical and scientific data bearing on the question of radiation hormesis. We find the data in support of most of the hormesis postulates intriguing but inconclusive.

Dose-Response Relationship, Radiation↗
PubMed1990

The radiotoxicology of Radithor. Analysis of an early case of iatrogenic poisoning by a radioactive patent medicine.

Radithor was a radioactive patent medicine that was touted as a metabolic stimulant and aphrodisiac. We have obtained several original samples of Radithor and have used these historical specimens and a computer-based calculation model to perform a retrospective analysis of a famous case of Radithor-related radium poisoning. Our data suggest that the victim's cumulative skeletal radiation dose may have exceeded 350 Sv by the time he died. This figure far exceeds most current estimates of what radiation exposure level would constitute a rapidly lethal dose if given acutely. The physiological response to longterm internal radiation exposure and the highly localized nature of alpha particle irradiation may require the development of new models for the assessment of risk in cases of internal alpha particle irradiation.

Bone and Bones↗
PubMed1990

Radithor and the era of mild radium therapy.

Soon after the discovery of radium, a school of practitioners arose who were interested primarily in the physiological rather than the tumoricidal powers of this new radioactive element. This treatment philosophy was called "mild radium therapy" and involved the oral or parenteral administration of microgram quantities of radium and its daughter isotopes, often as cures for rheumatic diseases, hypertension, and metabolic disorders. Manufacturers of patent medicines responded to this market by producing a variety of over-the-counter radioactive preparations including pills, elixirs, and salves. One such nostrum was Radithor, a popular and expensive mixture of radium 226 and radium 228 in distilled water. Radithor was advertised as an effective treatment for over 150 "endocrinologic" diseases, especially lassitude and sexual impotence. Over 400,000 bottles, each containing over 2 muCi (74 kBq) of radium, were apparently marketed and sold worldwide between 1925 and 1930. The death of the Pittsburgh millionaire sportsman Eben M. Byers, who was an avid Radithor user, by radium poisoning in 1932 brought an end to this era and prompted the development of regulatory controls for all radiopharmaceuticals.

Alpha Particles↗
PubMed1989

Alpha particle radio-immunotherapy: animal models and clinical prospects.

Short-lived isotopes that emit alpha particles have a number of physical characteristics which make them attractive candidates for radioimmunotherapy. Among these characteristics are high linear energy transfer and correspondingly high cytotoxicity; particle range limited to several cell diameters from the parent atom; low potential for repair of alpha-induced DNA damage; and low dependence on dose rate and oxygen enhancement effects. This report reviews the synthesis, testing and use in animal models of an alpha particle emitting radioimmunoconjugate constructed via the noncovalent chelation of Bismuth-212 to a monoclonal IgM antibody specific for the murine T cells/neuroectodermal surface antigen, Thy 1.2. These 212Bi-anti-Thy 1.2 immunoconjugates are capable of extraordinary cytotoxicity in vitro, requiring approximately three 212Bi-labeled conjugates per target cell to suppress 3H-thymidine incorporation to background levels. The antigen specificity afforded by the monoclonal antibody contributes a factor of approximately 40 to the radiotoxicity of the immunoconjugate. Animals inoculated with a Thy 1.2+ malignant ascites were cured of their tumor in an antigen-specific fashion by intraperitoneal doses of approximately 200 microCi per mouse. Alpha particle emitting radioimmunoconjugates show great potential for regional and intracavitary molecular radiotherapy.

Alpha Particles↗
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↗