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J L Humm

Publications and source records attributed to J L Humm.

66 records · Page 4Linked to original sources
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

Nonuniformity of tumor dose in radioimmunotherapy.

The conventional approach to calculating tumor radiation dose from internally administered radioisotopes is by the MIRD schema. The raw input data for such dose calculations is obtained by immunoscintigraphic methods, PLANAR or SPECT imaging. Limitations in the spatial resolution of these techniques can lead to a considerable underestimate of the gross variation in tumor dose. The use of radiolabeled monoclonal antibodies for therapy can result in large nonuniformities in tumor dose. This paper discusses how antibody distribution can influence the energy deposition in the nuclei of target cells. Heterogeneity of antibody binding will lead to an expected decrease in the effectiveness of the radiation delivered. However, enhanced cell killing is possible if the radiolabeled Ab binds to the cell surface membrane and may be further enhanced if the Ab is internalized. Calculations are presented for two cases: (a) a three-dimensional random packing arrangement of cells as a model of the astructural nondifferentiated form seen in some tumors, and (b) differentiated carcinoma of the colon with the cells in tubules. Results for the magnitude of the mean energy deposition to individual cell nuclei from: (a) cell membrane bound 211At, 199Au, 131I, and 90Y-labeled Abs, and (b) a uniform distribution of these sources, as a function of internuclear distance for the two histologies are presented. Energy deposition in tumor cell nuclei from membrane bound radiolabeled antibody may be several times greater than estimated with the assumption of a uniform source distribution.

Adenocarcinoma↗
PubMed1989

A new calculational method to assess the therapeutic potential of Auger electron emission.

This paper discusses a new computer code to estimate the efficacy of Auger electron sources in cancer therapy. Auger electron emission accompanies the decay of many radionuclides already commonly used in nuclear medicine, for example; 99mTc and 201Tl. The range of these electrons is in general sub-cellular, therefore, the toxicity of the source depends on the site of decay relative to the genetic material of the cell. Electron track structure methods have been used which enable the study of energy deposition from Auger sources down to the Angstrom level. A figure for the minimum energy required per single strand break is obtained by fitting our energy deposition calculations for 125I decays in a model of the DNA to experimental data on break lengths from 125I labeled plasmid fragments. This method is used to investigate the efficiency of double strand break production by other Auger sources which have potential value for therapy. The high RBE of Auger sources depends critically on the distance between the source and target material. The application of Auger emitters for therapy may necessitate a carrier molecule that can append the source to the DNA. Many DNA localizing agents are known in the field of chemotherapy, some of which could be carrier molecules for Auger sources; the halogenated thymidine precursors are under scrutiny in this field. The activation of Auger cascades in situ by high energy, collimated X ray and neutron beams is also assessed.

DNA, Neoplasm↗
PubMed1989

Calculation of initial yields of single- and double-strand breaks in cell nuclei from electrons, protons and alpha particles.

A model of the DNA and electron and ion track structure computer codes are used to model damage in the DNA by direct action. This damage is converted into single-strand breaks using the method described by Charlton and Humm (1988) in which a minimum energy deposited in a critical volume of the DNA is correlated with the production of single-strand breaks. It is then assumed that if these single-strand breaks lie on opposite strands and are separated by less than a few base pairs they produce double-strand breaks. Absolute yields of both single- and double-strand breaks expressed in breaks/Gy-dalton are calculated and compared to measured yields. Good agreement is obtained for single-strand breaks while the calculated yields for double-strand breaks are greater than those measured.

Alpha Particles↗
PubMed1988

A method of calculating initial DNA strand breakage following the decay of incorporated 125I.

Two sources of individual Auger electron spectra and an electron track code were used with a simple model of the DNA to successfully simulate the single-strand DNA breakage measured by Martin and Haseltine (1981). The conditions of the calculation were then extended to examine patterns of single-strand breaks in both strands of the DNA duplex to score double-strand breaks. The occurrences of five types of break were scored. The total number of double-strand breaks (dsb) per decay at the site of the decay was 0.90 and 0.65 for the different Auger electron spectra. It was shown that for mammalian cells an additional source of double-strand breaks from low LET radiation added approximately 0.17 dsb/decay to each, giving a final total of 1.07 and 0.85 dsb/decay for mammalian cells depending on the electron spectrum. Further is is shown that the energy deposition in the DNA from the iodine decay is very complex, with a broad range of energy depositions and products. Even for a particular energy deposited in the DNA different types of strand break are produced. These are identified and their probabilities calculated.

DNA↗
PubMed1988

A Monte-Carlo approach to the microdosimetry of 224Ra in murine compact and cancellous bone.

A method is described which allows dose calculations to be made to individual target cells in different regions of mouse bone marrow exposed to alpha particles emitted from bone. The method takes into account the variable rate of transfer of energy along the tracks of alpha particles and was applied to experiment-based values calculated for the concentration of 224Ra on bone surfaces after an injection of a leukemogenic amount of the nuclide. These calculations show a minimum dose of 11 Gy in small (less than 50-micron) marrow spaces and 10 Gy close to bone surface in the shaft of the femur. The results suggest that leukemogenic doses are likely to occur at some distance from bone surfaces in wide marrow spaces and that osteosarcoma is not likely to be induced directly in cells immediately aligning bone surfaces.

Absorption↗
PubMed1987

A microdosimetric model of astatine-211 labeled antibodies for radioimmunotherapy.

Astatine-211 is an alpha-emitter with a short half-life (7.2 hr). This paper discusses the potential of 211At targeted by antibodies for tumor therapy and the possible advantage of 211At over beta- and gamma-emitting radionuclides such as 131I currently employed in the field of radioimmunotherapy. Since the longest range alpha-particle from 211At is only 67 microns and the rate of energy loss is high (track averaged linear energy transfer LT approximately 120 keV/micron), a disintegration of 211At produces a large and extremely localized deposition of energy. A Monte-Carlo model has been developed for studying the stochastic fluctuation of alpha-particle hits and energy deposition in cell nuclei in an attempt to determine the efficacy of 211At-labeled antibodies for tumor cell inactivation. Calculations have been performed for 2 extreme conditions: (a) the case of 211At retained in the capillary, and (b) for a homogeneous distribution of 211At-labeled antibody in the tumor. The results of these two calculations represent the boundary conditions between which any real solution must lie. Finally, developments to the model to include antibody transport across the capillary membrane and through the tumor tissue are discussed.

Antibodies, Neoplasm↗
PubMed1986

Radioimmunotherapy of malignancy using antibody targeted radionuclides.

Antibodies directed against tumour associated antigens provide a means for delivering preferentially cytotoxic radionuclides to the cells of primary and secondary tumours. The factors that influence the effectiveness of the radiation in the tumour compared with its effect on the radiosensitive normal tissues include the specificity of the antibody, the distribution of targeted energy within the tumour and the host's response to the injected foreign antibody. Recently some encouraging results from clinical trials of radioimmunotherapy have been reported in the literature. There is a continual search for more avid and specific antibodies, and the techniques of genetic engineering are being applied to the problem of reducing the antigenicity and mass of the carrier antibody. The improved efficiency of the labelled antibody needs to be supplemented by an identification of those tumours most likely to respond to this form of therapy.

Animals↗
PubMed1986

Dosimetric aspects of radiolabeled antibodies for tumor therapy.

Radioimmunotherapy (RIT) is rapidly attracting interest as a potential new weapon in the arsenal for cancer therapy. This article concentrates on some of the dosimetric aspects affecting the potential success of RIT, and examines factors which influence the choice of a radiolabel for RIT. No radionuclide is likely to give an optimum tumor/nontumor insult for all tumor types; therefore, the concept of matching the source to tumor morphology is introduced. Lists of candidate radionuclides are given, classified according to the type of decay, range, and energy of the emission. The article examines how the choice of radionuclide for radiolabeling the antibody affects the local energy deposition in the tumor. Both the effect of tumor size on the energy absorbed fraction and the problem of antibody binding heterogeneity are discussed. The approach to RIT is to relate the choice of radionuclide to the physical properties of the tumor.

Alpha Particles↗
PubMedDate not supplied

Using positron emission tomography with [(18)F]FDG to predict tumor behavior in experimental colorectal cancer.

This study investigates the relationship between FDG uptake as determined by positron emission tomography (PET) imaging and rates of tumor growth, cellular GLUT1 transporter density, and the activities of hexokinase and glucose-6-phosphatase in a solid tumor implant model. Five different human colorectal xenografts of different growth properties were implanted in athymic rats and evaluated by dynamic (18)F-FDG-PET. The phosphorylating and dephosphorylating activities of the key glycolytic enzymes, hexokinase and glucose-6-phosphatase, were measured in these tumor types by spectrophotometric assays and the expression of GLUT1 glucose transporter protein was determined by immunohistochemistry. Correlations among FDG accumulation, hexokinase activity, and tumor doubling time are reported in these colon xenografts. The results indicate that the activity of tumor hexokinase may be a marker of tumor growth rate that can be determined by (18)F-FDG-PET imaging. PET scanning may not only be a useful tool for staging patients for extent of disease, but may provide important prognostic information concerning the proliferative rates of malignancies.

Animals↗
PubMedDate not supplied

Microdosimetric concepts in radioimmunotherapy.

In microdosimetry particular emphasis is placed on the stochastic fluctuation of dose in small target volumes such as individual cell nuclei or chromatin fiber, and their relevance to radiobiologic toxicity. Thus microdosimetry is intimately associated with models of radiation action. There are three principal areas where microdosimetry has been applied: (1) radiation protection, (2) high LET radiotherapy, e.g., neutron therapy, and (3) incorporated radionuclides, and in this latter category the importance of microdosimetry to the radiobiology of radiolabeled antibodies is becoming increasingly recognized. The objective of microdosimetry is the complete characterization of energy deposition within all target volumes throughout the tissue of interest. The importance and relevance of this pursuit will depend upon the properties of the radionuclide emissions and the spatial distribution of the radionuclide relative to the target volumes. If the distribution of internal emitters within both malignant and normal tissue is uniform, the application of microdosimetry to radioimmunotherapy (RIT) is limited to alpha-emitters and Auger emitters. Under such circumstances the traditional MIRD formalism for the evaluation of tumor and tissue doses from the commonly used beta-emitters is entirely adequate. This, however, is rarely the case. When the distribution of radiolabeled antibody is nonuniform, techniques of dose averaging over volumes greater in size than the individual target volumes can become inadequate predictors of the biological effect. The concepts, methods, and realm of applicability of microdosimetry within the field of radioimmunotherapy are emphasized in this paper.

Humans↗