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Nuclear Medicine Department
Project numbers
Development of Tumor-imaging Radiopharmaceuticals
Imaging Organ Function in Small Animals
Characterization of Tissue in MRI of Polymyocitis
Measurement of Myocardial Thickening
Alignment of CT and Nuclear Medicine Transmission Scans of the Thorax and Abdomen
Measurement of Global Ventricular Function from Gated Tomographic Images
Development of Quantitative Measures of Glucose Uptake for Tumor Imaging
Radiolabeled Monoclonal Antibody Imaging of Tumors
Correlative Imaging, Functional Imaging, and Technology Assessment of Nuclear Medicine Imaging Procedures
Enhancement of Renal Clearance of Tc-99m scdsFv by Chemical Modifications
Gene-specific Radiotherapy
Iterative Reconstruction for Optimizing Tumor Detection
Effect of Scatter Contamination of Transmission Data on Attenuation Corrected Cardiac Perfusion Images
Comparison of Attenuation Corrected and Noncorrected Whole Body Oncology Images
INTRAMURAL RESEARCH PROJECT Z01 CL-00101-03 NMRR
October 1, 1997 to September 30, 1998
Title of Project: Development of Tumor-imaging Radiopharmaceuticals
Principal Investigator: R.D. Neumann, M.D. (Chief)
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: W.C. Eckelman, Ph.D., PET, CC
L. Aloj, M.D., NM, CC
C. Caraco, M.D., PET, CC
Collaborating Units: NCI
Staff-Years: 1.25
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: In previous experiments we showed that the amount of Glut-1 glucose transporter protein and mRNA present in cells does not correlate with the ability of cells to accumulate 2-fluoro-2-deoxyglucose (FDG). We have since further characterized other biochemical properties of A431 cells (which express high levels of Glut-1) and T47D cells (which express low levels of Glut-1). Neither cell line expresses other glucose transporter isoforms at detectable levels by Northern blot analysis.
We have now over-expressed the Glut-1 glucose transporter in both these cell lines. In both lines we obtained levels of expression, at the mRNA level, that were 5 to 75 times higher than the wild-type cells. In A431 cells the amount of total Glut-1 protein was unchanged, suggesting some post-translational control of Glut-1 protein levels in these cells. In T47D cells, a 10-fold increase in the amount of total Glut-1 protein did not increase FDG uptake, while greatly increasing the ability of cells to transport 3-O-Methyl glucose, a glucose analogue that is not phosphorylated.
Studies of the mitochondrial phosphorylating activity towards FDG for these two cells show that mitochondria of A431 cells, which accumulate FDG at a lower rate than T47D cells, show a lower affinity for FDG (Km ~ 300 µM) compared with mitochondria of T47D cells (Km ~ 100 µM), and that for equal amounts of mitochondrial protein, the maximum velocity (Vmax) of FDG phosphorylation is two times faster for T47D preparations than for A431 preps. These data suggest a tighter control of FDG phosphorylating activity on FDG uptake, rather than FDG transport activity.
At the mRNA level, however, T47D cells show lower steady state levels of both the Hexokinase I and II transcripts, suggesting that phosphorylating activity does not correlate with the level of gene expression, or that, putatively, another hexokinase isoform may be present in T47D, thus providing higher levels of FDG phosphorylation in these cells. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-00401-10 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Imaging Organ Function in Small Animals
Principal Investigator: V. Green (Senior Investigator)
IPL, NMD, CC, NIH, Bethesda, MD 20892
Other Personnel: J. Seidel, NM, CC
J.J. Vaquero, NM, CC
S. Siegel, NM, CC
Collaborating Units: PI, NCRR (J. Sullivan)
CBEL, DCRT (C. Johnson)
PCB, DCRT (W.R. Gandler)
PET, CC (W.C. Eckelman, Ph.D.)
Staff-Years: 4
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: A positron emission tomography (PET) Buismuth Germinate Ortho (BGO) projection/tomographic imaging system was mechanically and electrically completed during this reporting period. The system is now undergoing additional refinements to improve imaging performance and user friendliness. Tests of the device to date have shown good agreement with predictions and the design goal of 2 mm spatial resolution in both projection and tomographic modes of operation has been achieved. The system is already being used in several mouse imaging projects to evaluate the effects of genetic changes on organ function.
Phoswich scintillator arrays comprised of combinations of Lutetium Silicate Ortho (LSO), GSO, LGSO, or BGO were coupled to miniature metal-can position-sensitive photomultiplier tubes (PSPMT) in order to determine which combination of these scintillators might best form a depth-of-interaction detector module for PET imaging. Although good results were obtained with almost all combinations, practical reasons suggest that a dual layer phoswich consisting of GSO and LGSO will best serve this purpose. The scintillator layer of photon interaction in such a module can be easily discerned by long and short integration of the last dynode signal, while the position of the event within the transverse field-of-view can be determined by the PSPMT. Components, including custom-made preamplifier boards, are now being procured for a stationary, small diameter ring-type small animal PET scanner based on these GSO/LGSO modules.
Progress continues to be made on an imaging probe system. A prototype probe with all necessary support electronics has been assembled and is now undergoing performance tests. Work was also continued to ascertain the imaging characteristics of a pair of continuous LSO slab scintillation cameras as candidates for a small animal imaging system. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-00410-05 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Characterization of Tissue in MRI of Polymyocitis
Principal Investigator: M. Bartlett, Ph.D. (Fogarty Fellow)
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: S. Bacharach, Ph.D., NM, CC
P. Plotz, M.D., Ph.D., NIAMS
P. Choyke, M.D., DR, CC
Collaborating Units: NIAMS (M. Villalba, M.D.)
Staff-Years: 1
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: Project completed with acceptance of paper. During this fiscal year, only time expended was in revisions to manuscript.
The NIAMS has an ongoing protocol to study polymyocitis. As part of this protocol, subjects are imaged with magnetic resonance imaging using a special pulse sequence that suppresses signal from fat, but enhances signal from diseased tissue. In the past, the images were usually evaluated visually to determine extent and progress of disease. A more quan-titative method for analysis has been developed and is being tested. This method produces a three-dimensional histogram of signal intensity values. In normal subjects this histogram is nearly gaussian in shape, while in abnormal subjects this histogram is skewed to higher intensity values. A method was developed to give quantitative indices of both degree of disease as well as volume of diseased tissue. This method is based on the assumption that the low signal intensity values within the tissue being studied represent normal tissue. The left half of the histogram is then reflected at about its peak to give an estimate of what the subject's histogram would have looked like if it were completely normal. Comparing the reflected histogram to the actual histogram allows estimates of degree and volume of disease. The method is now completed, and has been presented orally at the Society of Magnetic Resonance Imaging. A manuscript describing the methodology has been accepted, and will be published in September of 1998. The collaborating institute has begun using the method for evaluation of subjects with polymyocitis. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-00411-04 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Measurement of Myocardial Thickening
Principal Investigator: P. Brigger, Ph.D. (Fogarty Fellow)
BEIP, NCRR, NIH, Bethesda, MD 20892
Other Personnel: S. Bacharach, Ph.D., NM, CC
V. Dilsizian, M.D., NM, CC
Collaborating Units: DR, NHLBI (G. Srinivasan, M.D.)
BEIP, NCRR
Staff-Years: 0.03
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: T1-201 and Tc-MIBI imaging of the myocardium are two very commonly employed clinical tests to assess myocardial perfusion and viability. Recently it has been proposed to use ECG-gating techniques, to "gate" these images, in order to measure cardiac ventricular function. This ability to simultaneously measure both function and perfusion, without the need for additional imaging or injection of radioisotope, would have profound impact on cost and clinical efficacy. Reports have already appeared in the literature on methods to quantitate function from the low-noise, high resolution images obtainable from Tc-MIBI. However, the more commonly used perfusion agent T1-201 gives images with much higher noise levels, making quantification of function problematic. One of the difficulties is that poor contrast (associated with bloodpool activity, and trabeculae) makes endocardial borders hard to trace. We proposed using a new method for computation of ejection fraction, based on epicardial borders, using the constraint that myocardial mass must be constant. This proposal is being tested, using an in-house developed image processing system that uses dynamic programming to track the endo and epi cardial borders. Preliminary patient studies indicate that this method may permit extraction of functional information even from noisy T1-201 studies. A description and validation of the technique will be presented orally and in abstract form. The manuscript describing the technique and its validation has been accepted for publication, and will appear in early 1999.
This study was completed June 1998. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-00412-04 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Alignment of CT and Nuclear Medicine Transmission Scans of the Thorax and Abdomen
Principal Investigator: F. Jousse, M.D. (Fogarty Fellow)
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: S. Bacharach, Ph.D., NM, CC
C. Barker, Ph.D., NM, CC
J. Carrasquillo, M.D., NM, CC
B.A. Chodkowski, NM, CC
Collaborating Units: NCI; NCRR
Staff-Years: 0.75
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: Certain NCI protocol patients are imaged repetitively over the course of many days or weeks. For several reasons, it is desired to be able to: 1.) align the images from one imaging session to another; and 2.) align the two-dimensional (2D) nuclear medicine projection images with computer tomography (CT) images of the same subject. Alignment of projection images from one imaging session to another permits more accurate quantitation of changes in uptake over time. Aligning scans done on subsequent days also permits use of a single transmission scan to perform absolute quantitation. Alignment of the nuclear medicine projection images with the CT data permits correlation of radiopharmaceutical uptake with morphological structure. In addition, the CT data may themselves be used to perform attenuation correction of the emission data. An investigation of alignment scheme 1.) has been performed, using an adaptation of a technique previously published by our group for three-dimensional alignment of positron emission tomography data. The method was modified for alignment of 2D projection images, and uses maximal pixel to pixel correlation techniques, applied to the transmission scan. The method uses lung borders to optimize the alignment. The method has now been thoroughly tested on phantoms and with simulated and actual motion of patient data, and a manuscript has been submitted for publication. A new protocol involving several imaging modalities and tracers will begin shortly, and the method will be tested and applied to that protocol. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-00414-03 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Measurement of Global Ventricular Function from Gated Tomographic Images
Principal Investigator: P. Mansour (IRTA Fellow)
NHLBI, NIH, Bethesda, MD 20892
Other Personnel: S. Bacharach, Ph.D., NM, CC
C. Barker, Ph.D., NM, CC
V. Dilsizian, M.D., NM, CC
Collaborating Units: PET, CC
Cardiology, NHLBI
Staff-Years: 0.8
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: Current methods of determining global ventricular function depend on planar cardiac imaging techniques. In these techniques, activity in front of and behind the heart are superimposed upon left ventricle bloodpool activity. Physical constraints prevent images from being acquired along the true long axis of the left ventricle. Recent developments in gated single photon emission computerized tomography imaging have shown that it is possible, in approximately the same imaging time, to acquire fully three-dimensional images of the beating heart, and thus of ventricular function. In addition, recent developments in imaging technology have shown that ventricular function may be determined from gated perfusion or metabolism tomographic images. This project set out to determine the accuracy and feasibility of making such quantitative measurements. The first phase of the project (now complete) focused on gated blood pool studies, and found that by "reprojection" of the data into a true long axis planar slice, one could produce ejection fraction (EF) results which were both more accurate and potentially more reproducible, than existing EF techniques. This finding is expected to have significant impact on clinical studies (e.g., evaluation of adriamycin therapy) in which clinical decisions are based on small changes in ejection fraction over time. These results have recently been published. The second phase of this project is now beginning; namely, to use the tomographic data directly to compute regional, rather than simply global, function. This would permit direct correlation of regional function with perfusion or metabolism. This normal volunteer protocol is now approved and will begin in September of 1998. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-00415-02 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Development of Quantitative Measures of Glucose Uptake for Tumor Imaging
Principal Investigator: F. Jousse, M.D. (Fogarty Fellow)
CC, NIH, Bethesda, MD 20892
Other Personnel: S. Bacharach, Ph.D., NM, CC
G. Aloj, M.D., NM, CC
J. Carrasquillo, M.D., NM, CC
S. Libutti, M.D., DCT, NCI
Collaborating Units: NCI
Staff-Years: 1.2
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: Tumor growth and viability can be monitored by measuring the rate of glucose metabolism in the tumor, using fluorodeoxyglucose (FDG) positron emission tomography (PET). The goal of this imaging physics project is to assess various quantitative measures of tumor FDG uptake for this purpose, and if possible, as indices of response to therapy. It was postulated that the usual method for measuring glucose uptake--the so-called "Standardized Uptake Value"--would produce values that were too strongly influenced by the metabolic state of other body organs, and by the time of imaging. Instead, it was proposed to normalize the glucose uptake by the integral of the arterial deoxyglucose concentration curve. This curve is to be determined from a combination of cardiac bloodpool imaging (during the first 20 minutes post injection), and intravenous blood sampling (during the remainder of the study). The study is to use subjects undergoing PET FDG imaging for evaluation of colon cancer. In addition, previously acquired data from subjects undergoing FDG imaging for liver cancer will be analyzed. We are also investigating the possibility of using some "control" data from subjects who have previously undergone FDG cardiac imaging. The first phase of the project involves estimating the errors associated with using intravenous samples for late estimates of the arterial curve. The second phase will compare uptake values at early and late times in tumors and normal tissue using the proposed arterial curve normalization, and using the conventional scheme of normalization (lean body mass and injected activity). (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-00600-05 NMRR
October 1, 1997 to September 30, 1998
Title of Project: Radiolabeled Monoclonal Antibody Imaging of Tumors
Principal Investigator: J.A. Carrasquillo, M.D. (Deputy Chief)
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: C. Paik, Ph.D., NM, CC
M. Whatley, B.S., NM, CC
M. Rotman, Pharm., NM, CC
D. Drumm, Technologist, NM, CC
Collaborating Units: NCI, Metabolism Branch, DCS
NCI, Laboratory of Molecular Biology, DBS
NCI, Treatment
NCI, Surgery Branch, DCS
NCI (N. Le)
Staff-Years: 4.8
Human Subjects: x (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: These studies are designed to develop improved methods for detecting and treating malignancies. Our group performs preclinical evaluation of antibodies that appear to be promising after initial screening by various laboratories at the National Cancer Institute and develops these antibodies for clinical staff. They are then administered to patients under the supervision of a nuclear medicine physician and an assistant in the Nuclear Medicine Department. Serial blood samples, urine specimens, and often bone marrow or tumor biopsies are obtained to evaluate the distribution of the monoclonal antibody in the body.
We have completed all of the phase I trial with B3, in collaboration with Dr. Ira Pastan. A total of 26 patients were accrued.
Our collaborative radioimmunotherapy trial with Dr. Waldmann (PI) in which we used humanized anti-tac monoclonal antibody, is ongoing. We have accrued 18 patients with ATL or with non ATL T-cell lymphoma.
Imaging studies comparing the use of Tc-99m anti-CEA Fab (FDA approved) and F-18 deoxyglucose have been started in patients with previous history of colorectal carcinoma and rising CEA without evidence of disease by conventional radiographic modalities. We have studied 12 patients to date.
We have completed preclinical studies with radiolabeled immunotoxin developed by Dr. Pastan's Laboratory.
From the four stereosiomers of CHX-DTPA we have selected CHX-A1, the most stable for Y-90 chelation, as our preferred chelate for antibody trials. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-00900-02 NMCS
October 1, 1997 to September 30, 1998
Title of Project: Correlative Imaging, Functional Imaging, and Technology Assessment of Nuclear Medicine Imaging Procedures
Principal Investigator: J.C. Reynolds, M.D. (Senior Clinical Staff)
CSS, NMD, CC, NIH, Bethesda, MD 20892
Other Personnel: C.C. Chen, M.D., NMD, CC
M. Whatley, CNMT
C. Barker, Ph.D.
Collaborating Units: DRD, CC (J. Doppman, M.D.; N. Avila, M.D.)
DTM, CC (S. Leitman, M.D.)
NIDDK (R. Jensen, M.D.; M. Skarulis, M.D.)
NHLBI (S. Chu, M.D.)
NCI (S. Bates, M.D.; I. Magrath, M.D.)
NCI (M. Walther, M.D.)
Staff-Years: 1
Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither
x (a1) Minors
(a2) Interviews
Summary of Work: This is a support and development project related to several Clinical Protocols at the National Institutes of Health. Thirty to 50 percent of the patients studied by the Nuclear Medicine Department have benign or malignant tumors. Detection and localization of these tumors is important for surgical removal, for staging, and for assessing the effects of chemotherapy. Because Nuclear Medicine imaging is based on metabolic, biochemical, or vascular characteristics of tumors, its results are complementary to imaging procedures based on anatomy. Usually, Nuclear Medicine imaging is more sensitive for tumor detection than computer tomography (CT) or magnetic resonance imaging (MRI), but the Nuclear Medicine images often do not show adjacent tissues or organs, so the abnormality is imprecisely located. For optimal clinical care, Nuclear Medicine findings must often be correlated with CT or MRI images. Generally, this correlation is done at clinical conferences, but as new tumor localization radiopharmaceuticals are being developed, the department and section are working at electronically fusing tomographic Nuclear Medicine images with CT or MRI. Specific protocols where fusion of images may be important for clinical care include In-111 octreotide imaging of gastrinoma and other neuroendocrine tumors, Tc-99m sestamibi imaging of parathyroid tumors, and I-131 or I-123 MIBG imaging of pheochromocytoma. Nuclear Medicine also supports cancer therapy research by performing functional studies including: 1.) I-131 dosimetry of thyroid cancer; 2.) Tc-99m sestamibi imaging of p-glycoprotein activity which is related to the multidrug resistance gene; and 3.) In-111 labeled tumor seeking lymphocytes imaging. The department uses technology assessment methodology (receiver operating characteristics curve analysis, etc.) to evaluate the utility of various imaging procedures. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-02001-05 NMRR
October 1, 1997 through September 30, 1998
Title of Project: Enhancement of Renal Clearance of Tc-99m scdsFv by Chemical Modifications
Principal Investigator: J.A. Carrasquillo, M.D.
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: C.H. Paik, Ph.D., Radiopharmaceutical Chemist, NM, CC
M-K. Kim, M.D., Ph.D., NM, CC
H. Kobayashi, M.D., Ph.D., NM, CC
N. Le, NM, CC
Collaborating Units: Laboratory of Molecular Biology, Division of Basic Sciences,
NCI (I. Pastan, M.D.)
Staff-Years: 3
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: This project was developed and is directed by C.H. Paik, Ph.D. We have been developing chemical methods to radiolabel monoclonal antibodies and their fragments to use them as scintigraphic imaging agents to detect hematologic malignancies that express IL-2a receptors. For FY '98 we have extended our efforts to label genetically synthesized single chain, disulfide stabilized variable-region fragment (scdsFv) of antiTac monoclonal antibody with Tc-99m. The biodistribution of scdsFv was similar to that of dsFv, with its rapid tumor uptake whereas clearing rapidly from blood and all organs except kidneys. To improve its pharmacokinetic property with respect to its high renal uptake, we lowered the isoelectric point (pI 10) of scdsFv by acylation of its amino groups with succinic anhydride. This reaction neutralizes one positive charge on an amino group of scdsFv and at the same time adds one negative charge to dsFv. The succinic acid conjugated, Tc-99m-labeled scdsFv with a pI range of 4.4-6.4 showed the renal accumulation three to four times lower than that of the control Tc-99m-labeled scdsFv in tumor-bearing nude mice whereas its tumor uptake was not affected. Similarly, the whole-body retention of the succinic acid conjugate was much lower. The IL-2 receptor-positive ATAC4 tumor to non-tumor ratios increased steadily over time with ratios of 14.0, 13.6, 7.0, 22.8, 1.5, and 0.13 at 180 minutes for blood, the receptor-negative A431 tumor, liver, spleen, intestine, and kidney. This study suggests that the renal uptake of scdsFv involves charge interactions between positively charged scdsFv and negatively charged phopholipid bilayers of renal parenchymal cell membranes and that the lowering of the pI decreases the renal uptake. In conclusion, this study indicates that the high renal uptake of scdsFv can be optimized by chemical modifications without compromising tumor uptake. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-60001-03 NMRR
October 1, 1997 to September 30, 1998
Title of Project: Gene-specific Radiotherapy
Principal Investigator: R.D. Neumann, M.D. (Chief)
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: I. Panyutin, Ph.D.
V. Karamychev, Ph.D.
O. Sedelnikova, Ph.D.
A. Luu
T. Winters, Ph.D.
I. V. Panyutin, M.D.
K. Mezhevaya, Ph.D.
Y. Voloshin
Collaborating Units: NCI (V. Zhurkin, Ph.D.); NIDDK (V. Malkov, Ph.D.)
Univ. of Illinois (S. Mirkin, Ph.D.)
Epoch Pharmaceuticals (M. Reed, Ph.D.)
Somagenics Inc. (S. Kazakov, Ph.D.)
Staff-Years: 6.5
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: The goal of this project is to develop therapeutic radiopharmaceuticals based on targeting the decay of Auger electron emitting radioisotopes to specific sequences in DNA (genes) using triplex forming oligonucleotides (TFOs) as delivery vehicles.
In in vitro studies we have demonstrated that TFOs are able to deliver Auger electron emitters to specific targets in cellular DNA in order to inactivate genes and/or kill the cells containing the target sequences. Decay of I=125 in TFOs results in strand breaks in both strands of the target DNA with an efficiency from 0.4-0.8 break/decay. Higher efficiency can be achieved with radionuclide multiple labeling. Breaks are confined to the triplex target sequence, and 90 percent of the sequence specific breaks are located within 10 bp around the decay site. Specificity of TFOs was shown to be high enough to specifically break genomic DNA in a target located in a single copy gene. A liposome delivery system has been developed to effectively deliver radiolabeled TFOs into the cell nucleus. Radiotoxicity of TFOs delivered into the cell nucleus as measured by clonogenic assay is 300 times less than that of DNA-incorporated IUdR=125.
We have developed a rapid procedure for incorporation of the short life Auger electron emitters I=125 and In=111 into ODNs and demonstrated that decay of these clinically relevant radioisotopes produces DNA breaks with the yield comparable with that of I=125.
A new generation of chemically modified TFOs with increased in vivo stability permitting one step labeling with Auger electron emitters is being developed.
We have also shown that the fine structure of DNA damage by decay of Auger electron emitter depends on local DNA conformation and, therefore, by analyzing the DNA damage one can obtain information on the structure of DNA in nucleoprotein complexes both in vitro and in vivo. Based on this principle a new method of radioprobing of DNA-protein complexes has been demonstrated in several model systems.
In addition, studies have been initiated to investigate the mechanisms of Auger electron-induced DNA strand break repair in human cells. We have developed efficient methods of producing and isolating specific forms (form I and form II) of damaged shuttle vector plasmid DNA, using both oxidative agents and TFO-bound Auger emitting radionuclides as damaging agents. A liposome delivery system has been developed for efficient delivery of damaged DNA into human cells in order to evaluate the in vivo repairability and mutagenicity of site-specific DNA double strand breaks induced by I=125-labeled TFOs. Methods have been developed to recover Auger emitter damaged DNA following intracellular repair in human cells, and evaluate the mutational spectrum and the overall mutagenicity of the Auger emitter induced DNA double strand breaks.
In vitro double strand break (DSB) repair assays have been developed to permit isolation of human proteins involved in DSB repair from cell free extracts. Products of reactions using proteins identified by this assay will be examined at the molecular level and compared with products of DNA repaired in vivo role in overall DSB repair.
The aim of these studies is to identify the human repair pathways involved in Auger emitter induced DSB repair, assess the consequences of repairing these lesions, and to examine methods by which these repair processes may be manipulated to augment the radiotherapeutic effects of Auger electron emitting TFOs. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-70001-01 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Iterative Reconstruction for Optimizing Tumor Detection
Principal Investigator: C. Riddell, Ph.D. (Fogarty Visiting Fellow)
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: S. Bacharach, Ph.D., NM, CC
J. Carrasquillo, M.D., NM, CC
S. Libutti, M.D., NCI
Collaborating Units: NCI, Surgical Branch
Staff-Years: 0.6
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: It has long been known that iterative reconstruction algorithms produce different noise characteristics than those produced from the standard filtered backprojection algorithms. This project was undertaken to determine if these noise characteristics would improve the detectability of tumors in positron emission tomography studies using 18-FDG. Initial studies used a novel technique of "gated replicates" which permitted actual measurements of noise in patient studies. By comparing the intensity of the signal from tumors to the noise in the tumor region and to the noise in surrounding background regions, it was found that signal to noise improved markedly with use of the expectation maximization algorithm. The results were striking enough to warrant acquiring all further oncology studies using this reconstruction program. The algorithm has been implemented for preliminary clinical use. The preliminary results of the study were accepted for oral presentation, and a full manuscript is under preparation. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-70002-01 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Effect of Scatter Contamination of Transmission Data on Attenuation Corrected Cardiac Perfusion Images
Principal Investigator: C. Riddell, Ph.D. (Fogarty Visiting Fellow)
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: S. Bacharach, Ph.D., NM, CC
V. Dilsizian, M.D., NM, CC
Collaborating Units: NHLBI
Staff-Years: 0.6
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: Attenuation correction has recently been proposed in order to increase sensitivity and specificity for Tc-99m MIBI perfusion scans. However, the initial publications validating this increase in sens/spec with attenuation correction used a specially designed system that avoided the possibility of scattered Tc photons contaminating the attenuation data. The commercially implemented versions of this system do not avoid this possibility of contamination. We sought to measure the effect of this contamination on clinical cardiac studies, in order to determine how accurate a correction was necessary to achieve a clinically accurate perfusion image. Preliminary results for this project were accepted for oral presentation at the Society of Nuclear Medicine meeting in June, 1998. A full manuscript is being prepared. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-70003-01 NMIP
October 1, 1997 to September 30, 1998
Title of Project: Comparison of Attenuation Corrected and Noncorrected Whole Body Oncology Images
Principal Investigator: C. Riddell, Ph.D. (Fogarty Visiting Fellow)
NM, CC, NIH, Bethesda, MD 20892
Other Personnel: S. Bacharach, Ph.D., NM, CC
J. Carrasquillo, M.D., NM, CC
S. Libutti, M.D., NCI
Collaborating Units: NCI, Surgical Branch
Staff-Years: 0.6
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: Many whole body oncology studies using positron emission tomography (PET) are performed without correcting for the effects of attenuation. Whether this improves or degrades the detection of tumors has been the subject of much discussion. This project was undertaken to determine the effect of attenuation correction (AC) on the detectability of tumors in PET studies using 18-FDG. The method used employed a novel technique of "gated replicates" which permitted actual measurments of noise in patient studies, with and without AC. By comparing the intensity of the signal from tumors to the noise in the tumor region and to the noise in surrounding background regions, it was found that expected tumor detectability would be optimum using AC in the central portions of the body, while using no AC was optimum only in peripheral regions of the body, and in portions of the lung. If the AC were combined with an iterative reconstruction algorithm, however, the AC method was superior to the no-AC method at all locations of the body studied. The preliminary results of the study were accepted for oral presentation, and a full manuscript is under preparation. (Return to project list)